Drug Information

Drug (ID: DG00300) and It's Reported Resistant Information

Name	Oxaliplatin
Synonyms	Eloxatin (TN); Medac (TN); Oxaliplatin (TN); Oxaliplatin (JAN/USAN/INN) Click to Show/Hide
Indication	In total 1 Indication(s) Colorectal cancer [ICD-11: 2B91] Approved [1]
Structure
Drug Resistance Disease(s)	Disease(s) with Clinically Reported Resistance for This Drug (10 diseases) Colon cancer [ICD-11: 2B90] [2] Colorectal cancer [ICD-11: 2B91] [3] Esophageal cancer [ICD-11: 2B70] [4] Gastric cancer [ICD-11: 2B72] [5] Liver cancer [ICD-11: 2C12] [6] Neuroendocrine carcinoma [ICD-11: 2D4Y] [9] Oesophagogastric cancer [ICD-11: 2B71] [10] Oral squamous cell carcinoma [ICD-11: 2B6E] [11] Ovarian cancer [ICD-11: 2C73] [12] Pancreatic cancer [ICD-11: 2C10] [13] *Disease(s) with Resistance Information Validated by in-vivo* Model for This Drug (1 diseases) Liver cancer [ICD-11: 2C12] [7] Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug** (10 diseases) Melanoma [ICD-11: 2C30] [8] Chronic myeloid leukemia [ICD-11: 2A20] [14] Colon cancer [ICD-11: 2B90] [15] Colorectal cancer [ICD-11: 2B91] [16] Esophageal cancer [ICD-11: 2B70] [10] Gastric cancer [ICD-11: 2B72] [17] Liver cancer [ICD-11: 2C12] [18] Pancreatic cancer [ICD-11: 2C10] [13] Prostate cancer [ICD-11: 2C82] [14] Solid tumour/cancer [ICD-11: 2A00-2F9Z] [19]
Target	Human Deoxyribonucleic acid (hDNA)	NOUNIPROTAC	[1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula	C8H14N2O4Pt
IsoSMILES	C1CC[C@H]([C@@H](C1)[NH-])[NH-].C(=O)(C(=O)O)O.[Pt+2]
InChI	1S/C6H12N2.C2H2O4.Pt/c7-5-3-1-2-4-6(5)8;3-1(4)2(5)6;/h5-8H,1-4H2;(H,3,4)(H,5,6);/q-2;;+2/t5-,6-;;/m1../s1
InChIKey	DRMCATBEKSVAPL-BNTLRKBRSA-N
PubChem CID	9887053
TTD Drug ID	D0Y3ME
DrugBank ID	DB00526

Type(s) of Resistant Mechanism of This Drug

ADTT: Aberration of the Drug's Therapeutic Target

EADR: Epigenetic Alteration of DNA, RNA or Protein

IDUE: Irregularity in Drug Uptake and Drug Efflux

MRAP: Metabolic Reprogramming via Altered Pathways

RTDM: Regulation by the Disease Microenvironment

UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Click to Show/Hide the Resistance Disease of This Class

Colorectal cancer [ICD-11: 2B91]

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1)				[20]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Colorectal cancer [ICD-11: 2B91]
The Specified Disease	Colorectal carcinoma
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.67E-06 Fold-change: -9.64E-02 Z-score: -4.72E+00
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vitro Model	HCT8 cells	Colon	Homo sapiens (Human)	CVCL_2478
In Vivo Model	Mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Colony formation assay
Mechanism Description	miR139-5p reverses CD44+/CD133+-associated multidrug resistance by downregulating NOTCH1 in colorectal carcinoma cells.
Key Molecule: RalA-binding protein 1 (RALBP1)				[56]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	NCM460 cells	Colon	Homo sapiens (Human)	CVCL_0460
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis; Luciferase reporter assay
Experiment for Drug Resistance	CCK8 assay; Flow cytometric analysis
Mechanism Description	The ectopic overexpression of miR340 in CRC cell lines resulted in growth inhibition, apoptosis and enhanced chemosensitivity in vitro and in vivo, which was mediated by directly targeting RLIP76.
Key Molecule: Adhesion G-protein coupled receptor V1 (ADGRV1)				[57]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HCT116/L-OHP cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR145 inhibits drug resistance to L-OHP of HCT116 cells through suppressing the expression of target gene GPR98.
Key Molecule: Bcl-2-binding component 3 (BBC3)				[58]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	P53/PUMA signaling pathway		Activation	hsa04115
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis; Luciferase reporter assay
Experiment for Drug Resistance	TUNEL and ki67 staining; Caspase-3 activity assay; MTT assay
Mechanism Description	miR503-5p induces oxaliplatin resistance through the inhibition of apoptosis by reducing PUMA expression, which could direct target by miR503-5p. P53 suppresses miR503-5p expression.
Key Molecule: G1/S-specific cyclin-D2 (CCND2)				[60]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	HEY cells	Ovary	Homo sapiens (Human)	CVCL_0297
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Flow cytometry assay; MTS assay
Mechanism Description	miR141 inhibited CRC cell proliferation via targeting cyclin D2, which is involved in cell cycle regulation, and inhibited the mainte.nce of CSC stemness, thereby enhancing drug susceptibility.
Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP)				[61]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
Cell Pathway Regulation	Cell viability		Inhibition	hsa05200
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
In Vivo Model	BALB/c nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	The recovery of miR-122 expression can sensitize SW480/OR and HT29/OR cells to oxaliplatin-mediated apoptosis through the inhibition of XIAP expression.
Key Molecule: Programmed cell death protein 4 (PDCD4)				[43]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
Cell Pathway Regulation	Cell viability		Inhibition	hsa05200
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Overexpression of MEG3 improved oxaliplatin sensitivity of HT29/OXA and HCT116/OXA cells via suppressing miR-141 expression and upregulating PDCD4.
Key Molecule: Forkhead box protein O1 (FOXO1)				[62]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
	FOXO1 signaling pathway		Activation	hsa04068
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
In Vivo Model	BALB/c nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Knockdown of Mir-135b Sensitizes Colorectal Cancer Cells to Oxaliplatin-Induced Apoptosis Through Increase of FOXO1.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2)				[70]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	BCL2 signaling pathway		Regulation	N.A.
	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	RkO cells	Colon	Homo sapiens (Human)	CVCL_0504
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	LS174T cells	Colon	Homo sapiens (Human)	CVCL_1384
	COLO205 cells	Colon	Homo sapiens (Human)	CVCL_F402
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Transwell assay
Mechanism Description	BCL2 is a direct target of miR-139-5p in colorectal cancer cells and showed that the tumour suppressor activity of miR-139-5p is mediated by the modulation of BCL2 expression. BCL2 family proteins regulate and contribute to programmed cell death or apoptosis. The cell apoptosis results showed the induction of apoptotic cells contributed greatly to 5-Fu and OXA drug sensitivity, which was consistent with the multidrug resistance mechanisms. miR-139-5p is downregulated in colorectal cancer cells and tissues, and its inhibitory effects on cell migration, invasion, and drug sensitivity are mediated by the downregulation of its target BCL2.
Key Molecule: Programmed cell death protein 10 (PDCD10)				[63]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CellTiter-Glo assay
Mechanism Description	miR-425-5p is up-regulated in HCT116-R cells with acquired resistance to 5-fluouracil and OX compared with the parental HCT116 cells. Inhibition of miR-425-5p increases sensitivity to anti-cancer drugs by regulating apoptosis-related protein PDCD10 both in vitro and in vivo.
Key Molecule: Ras-related protein Rab-22A (RAP22A)				[64]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	miR204-5p/RAB22A signaling pathway		Regulation	N.A.
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	DLD1 cells	Colon	Homo sapiens (Human)	CVCL_0248
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	CaCo2 cells	Colon	Homo sapiens (Human)	CVCL_0025
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	HCT8 cells	Colon	Homo sapiens (Human)	CVCL_2478
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR-204-5p is frequently downregulated in colorectal cancer tissues, and survival analysis showed that the downregulation of miR-204-5p in colorectal cancer was associated with poor prognoses. Ectopic miR-204-5p expression repressed colorectal cancer cell growth both in vitro and in vivo. Moreover, restoring miR-204-5p expression inhibited colorectal cancer migration and invasion and promoted tumor sensitivity to chemotherapy. Mechanistic investigations revealed that RAB22A, a member of the RAS oncogene family, is a direct functional target of miR-204-5p in colorectal cancer. Furthermore, RAB22A protein levels in colorectal cancer tissues were frequently increased and negatively associated with miR-204-5p levels and survival time.
Key Molecule: Insulin-like growth factor 1 receptor (IGF1R)				[65]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell migration		Activation	hsa04670
	Cell proliferation		Inhibition	hsa05200
	PI3K/AKT/HIF-1/VEGF signaling pathway		Activation	hsa04151
In Vitro Model	SW1116 cells	Colon	Homo sapiens (Human)	CVCL_0544
In Vivo Model	BALB/c nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Overexpression of miR-143 inhibited cell proliferation, migration, tumor growth and angiogenesis and increased chemosensitivity to oxaliplatin treatment in an IGF-IR-dependent manner.
Key Molecule: TNF alpha converting enzyme (ADAM17)				[66]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vitro Model	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	ADAM-17 (a desintegrin and metalloproteases 17) is a novel multidrug resistance (MDR) mechanism in multidrug-resistant colorectal carcinoma (CRC). The presence of miR-222 was consistently inversely proportionate to the expression levels of ADAM-17. The loss of miR-222 in the HCT116/L-OHP and HCT-8/VCR MDR cell lines contributed to the overexpression of ADAM-17 and sensitized the HCT116/L-OHP and HCT-8/VCR MDR cells to some anticancer drugs.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2)				[68]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vitro Model	HCT-116/L-OHP cells	Kidney	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	Elevated levels of miR-1915 in the mimics-transfected HCT116/L-OHP cells reduced Bcl-2 protein level and the luciferase activity of a Bcl-2 3'-untranslated region-based reporter, and also sensitized these cells to some anticancer drugs. miR-1915 could play a role in the development of MDR in colorectal carcinoma cells at least in part by modulation of apoptosis via targeting Bcl-2.
Key Molecule: Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2)				[69]
Sensitive Disease	Colorectal adenocarcinoma [ICD-11: 2B91.2]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
In Vitro Model	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-20a overexpression resulted in resistance to these chemotherapy agents, while miR-20a knockdown led to sensitization, miR-20a down-regulated both BNIP2 mRNA and BNIP2 protein levels. miR-20a down-regulated the expression of the proapoptotic factor BNIP2, leading to an imbalance of anti-apoptosis and pro-apoptosis factors, resulting in the blockage of events leading to apoptosis.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-340				[56]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	NCM460 cells	Colon	Homo sapiens (Human)	CVCL_0460
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometric analysis
Mechanism Description	The ectopic overexpression of miR340 in CRC cell lines resulted in growth inhibition, apoptosis and enhanced chemosensitivity in vitro and in vivo, which was mediated by directly targeting RLIP76.
Key Molecule: hsa-mir-145				[57]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HCT116/L-OHP cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR145 inhibits drug resistance to L-OHP of HCT116 cells through suppressing the expression of target gene GPR98.
Key Molecule: hsa-miR-503-5p				[58]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	P53/PUMA signaling pathway		Activation	hsa04115
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	TUNEL and ki67 staining; Caspase-3 activity assay; MTT assay
Mechanism Description	miR503-5p induces oxaliplatin resistance through the inhibition of apoptosis by reducing PUMA expression, which could direct target by miR503-5p. P53 suppresses miR503-5p expression.
Key Molecule: hsa-mir-506				[59]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Wnt/Beta-catenin signaling pathway		Inhibition	hsa04310
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vitro Model	HCT116-OxR cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometric analysis
Mechanism Description	miR-506 overexpression in HCT116-OxR cells enhances oxaliplatin sensitivity by inhibiting MDR1/P-gp expression via down-regulation of the Wnt/beta-catenin pathway.
Key Molecule: hsa-mir-141				[60]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	HEY cells	Ovary	Homo sapiens (Human)	CVCL_0297
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	Flow cytometry assay; MTS assay
Mechanism Description	miR141 inhibited CRC cell proliferation via targeting cyclin D2, which is involved in cell cycle regulation, and inhibited the mainte.nce of CSC stemness, thereby enhancing drug susceptibility.
Key Molecule: hsa-miR-139-5p				[20]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vitro Model	HCT8 cells	Colon	Homo sapiens (Human)	CVCL_2478
In Vivo Model	Mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Colony formation assay
Mechanism Description	miR139-5p reverses CD44+/CD133+-associated multidrug resistance by downregulating NOTCH1 in colorectal carcinoma cells.
Key Molecule: hsa-mir-122				[61]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
Cell Pathway Regulation	Cell viability		Inhibition	hsa05200
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
In Vivo Model	BALB/c nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	The recovery of miR-122 expression can sensitize SW480/OR and HT29/OR cells to oxaliplatin-mediated apoptosis through the inhibition of XIAP expression.
Key Molecule: hsa-mir-141				[43]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
Cell Pathway Regulation	Cell viability		Inhibition	hsa05200
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Overexpression of MEG3 improved oxaliplatin sensitivity of HT29/OXA and HCT116/OXA cells via suppressing miR-141 expression and upregulating PDCD4.
Key Molecule: Maternally expressed 3 (MEG3)				[43]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
Cell Pathway Regulation	Cell viability		Inhibition	hsa05200
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Overexpression of MEG3 improved oxaliplatin sensitivity of HT29/OXA and HCT116/OXA cells via suppressing miR-141 expression and upregulating PDCD4.
Key Molecule: hsa-mir-135b				[62]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
	FOXO1 signaling pathway		Activation	hsa04068
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
In Vivo Model	BALB/c nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Knockdown of Mir-135b Sensitizes Colorectal Cancer Cells to Oxaliplatin-Induced Apoptosis Through Increase of FOXO1.
Key Molecule: hsa-miR-425-5p				[63]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CellTiter-Glo assay
Mechanism Description	miR-425-5p is up-regulated in HCT116-R cells with acquired resistance to 5-fluouracil and OX compared with the parental HCT116 cells. Inhibition of miR-425-5p increases sensitivity to anti-cancer drugs by regulating apoptosis-related protein PDCD10 both in vitro and in vivo.
Key Molecule: hsa-miR-204-5p				[64]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	miR204-5p/RAB22A signaling pathway		Regulation	N.A.
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	DLD1 cells	Colon	Homo sapiens (Human)	CVCL_0248
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	CaCo2 cells	Colon	Homo sapiens (Human)	CVCL_0025
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	HCT8 cells	Colon	Homo sapiens (Human)	CVCL_2478
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR-204-5p is frequently downregulated in colorectal cancer tissues, and survival analysis showed that the downregulation of miR-204-5p in colorectal cancer was associated with poor prognoses. Ectopic miR-204-5p expression repressed colorectal cancer cell growth both in vitro and in vivo. Moreover, restoring miR-204-5p expression inhibited colorectal cancer migration and invasion and promoted tumor sensitivity to chemotherapy. Mechanistic investigations revealed that RAB22A, a member of the RAS oncogene family, is a direct functional target of miR-204-5p in colorectal cancer. Furthermore, RAB22A protein levels in colorectal cancer tissues were frequently increased and negatively associated with miR-204-5p levels and survival time.
Key Molecule: hsa-mir-143				[65]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	PI3K/AKT/HIF-1/VEGF signaling pathway		Activation	hsa04151
In Vitro Model	SW1116 cells	Colon	Homo sapiens (Human)	CVCL_0544
In Vivo Model	BALB/c nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Overexpression of miR-143 inhibited cell proliferation, migration, tumor growth and angiogenesis and increased chemosensitivity to oxaliplatin treatment in an IGF-IR-dependent manner.
Key Molecule: hsa-mir-222				[66]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vitro Model	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	ADAM-17 (a desintegrin and metalloproteases 17) is a novel multidrug resistance (MDR) mechanism in multidrug-resistant colorectal carcinoma (CRC). The presence of miR-222 was consistently inversely proportionate to the expression levels of ADAM-17. The loss of miR-222 in the HCT116/L-OHP and HCT-8/VCR MDR cell lines contributed to the overexpression of ADAM-17 and sensitized the HCT116/L-OHP and HCT-8/VCR MDR cells to some anticancer drugs.
Key Molecule: hsa-miR-297				[67]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vitro Model	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
Experiment for Molecule Alteration	RT-PCR; qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	MRP-2 (MDR-associated protein 2) is an important MDR protein in platinum-drug-resistance cells, miR-297 in MDR colorectal carcinoma cells reduced MRP-2 protein level and sensitized these cells to anti-cancer drugs in vitro and in vivo.
Key Molecule: hsa-mir-1915				[68]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vitro Model	HCT-116/L-OHP cells	Kidney	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	Elevated levels of miR-1915 in the mimics-transfected HCT116/L-OHP cells reduced Bcl-2 protein level and the luciferase activity of a Bcl-2 3'-untranslated region-based reporter, and also sensitized these cells to some anticancer drugs. miR-1915 could play a role in the development of MDR in colorectal carcinoma cells at least in part by modulation of apoptosis via targeting Bcl-2.
Key Molecule: hsa-mir-20a				[69]
Sensitive Disease	Colorectal adenocarcinoma [ICD-11: 2B91.2]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
In Vitro Model	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-20a overexpression resulted in resistance to these chemotherapy agents, while miR-20a knockdown led to sensitization, miR-20a down-regulated both BNIP2 mRNA and BNIP2 protein levels. miR-20a down-regulated the expression of the proapoptotic factor BNIP2, leading to an imbalance of anti-apoptosis and pro-apoptosis factors, resulting in the blockage of events leading to apoptosis.
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1)				[59]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Wnt/Beta-catenin signaling pathway		Inhibition	hsa04310
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vitro Model	HCT116-OxR cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	Western blot analysis; Immunofluorescence staining assay
Experiment for Drug Resistance	MTT assay; Flow cytometric analysis
Mechanism Description	miR-506 overexpression in HCT116-OxR cells enhances oxaliplatin sensitivity by inhibiting MDR1/P-gp expression via down-regulation of the Wnt/beta-catenin pathway.
Key Molecule: ATP-binding cassette sub-family C2 (ABCC2)				[67]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vitro Model	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	MRP-2 (MDR-associated protein 2) is an important MDR protein in platinum-drug-resistance cells, miR-297 in MDR colorectal carcinoma cells reduced MRP-2 protein level and sensitized these cells to anti-cancer drugs in vitro and in vivo.
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: Aldolase B, fructose-bisphosphate (Aldolase B)				[48]
Metabolic Type	Glucose metabolism
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vivo Model	CRC patients			Homo Sapiens
Experiment for Molecule Alteration	Immunohistochemical (IHC) staining
Experiment for Drug Resistance	Overall survival assay (OS)
Mechanism Description	This study has demonstrated that overexpression of ALDOB in CRC cells promotes lactagenesis by regulating PDK1 activation. The secreted lactate is then transported to neighboring cells and converted to pyruvate by lactate-induced LDHB, enhancing the ability of OXPHOS in terms of basal respiration and acting as a repressor of CEACAM6 expression. Consequently, ALDOB/lactate-mediated expression of CEACAM6 promotes cell proliferation and 6-FU chemoresistance in CRC cells.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: hsa-mir-218				[53]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	FHC cells	Colon	Homo sapiens (Human)	CVCL_3688
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
Experiment for Molecule Alteration	RT-PCR; qRT-PCR
Experiment for Drug Resistance	Boyden chambers cell migration and invasion assays
Mechanism Description	miR218 is a tumor-suppressor gene and could significantly suppress the EMT process, miR218 promoted cell apoptosis and enhanced 5-FU-based chemosensitivity in colorectal cancer cells by targeting BIRC5.
Key Molecule: hsa-miR-139-5p				[70]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	BCL2 signaling pathway		Regulation	N.A.
	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	RkO cells	Colon	Homo sapiens (Human)	CVCL_0504
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	LS174T cells	Colon	Homo sapiens (Human)	CVCL_1384
	COLO205 cells	Colon	Homo sapiens (Human)	CVCL_F402
In Vivo Model	Mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Transwell assay
Mechanism Description	BCL2 is a direct target of miR-139-5p in colorectal cancer cells and showed that the tumour suppressor activity of miR-139-5p is mediated by the modulation of BCL2 expression. BCL2 family proteins regulate and contribute to programmed cell death or apoptosis. The cell apoptosis results showed the induction of apoptotic cells contributed greatly to 5-Fu and OXA drug sensitivity, which was consistent with the multidrug resistance mechanisms. miR-139-5p is downregulated in colorectal cancer cells and tissues, and its inhibitory effects on cell migration, invasion, and drug sensitivity are mediated by the downregulation of its target BCL2.

Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: GIHCG inhibitor of miR-200b/200a/429 expression (GIHCG)				[38]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
In Vitro Model	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	Long noncoding RNA GIHCG induces cancer progression and chemoresistance and indicates poor prognosis in colorectal cancer.
Key Molecule: piR-hsa-54265				[39]
Resistant Disease	Colorectal adenocarcinoma [ICD-11: 2B91.2]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
	Cell proliferation		Activation	hsa05200
	STAT3 signaling pathway		Activation	hsa04550
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vitro Model	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	CCK8 assay; Colony formation assays
Mechanism Description	piR-54265 binds PIWIL2 promotes CRC cell proliferation and invasiveness and 5-FU and oxaliplatin resistance via promoting oncogenic STAT3 signaling.
Key Molecule: hsa-let-7a				[40]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	RkO cells	Colon	Homo sapiens (Human)	CVCL_0504
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Colony formation assay; Transwell assays and wound healing assay; Flow cytometry assay
Mechanism Description	ANRIL promotes chemoresistance via disturbing expression of ABCC1 by inhibiting the expression of Let-7a in colorectal cancer.
Key Molecule: hsa-mir-216b				[41]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	PI3K/PTEN/AKT signaling pathway		Regulation	N.A.
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	HCT8 cells	Colon	Homo sapiens (Human)	CVCL_2478
	COLO 205 cells	Colon	Homo sapiens (Human)	CVCL_0218
	CCD-18Co cells	Colon	Homo sapiens (Human)	CVCL_2379
	COLO-678 cells	Colon	Homo sapiens (Human)	CVCL_1129
	HT55 cells	Colon	Homo sapiens (Human)	CVCL_1294
	LS1034 cells	Colon	Homo sapiens (Human)	CVCL_1382
	SW1417 cells	Colon	Homo sapiens (Human)	CVCL_1717
	SW403 cells	Colon	Homo sapiens (Human)	CVCL_0545
	SW48 cells	Colon	Homo sapiens (Human)	CVCL_1724
In Vivo Model	BALB/c mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR-216b promotes cell growth and enhances chemosensitivity of colorectal cancer by suppressing PDZ-binding kinase.
Key Molecule: hsa-mir-218				[42]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HEK293T cells	Kidney	Homo sapiens (Human)	CVCL_0063
	HCT-116/L-OHP cells	Kidney	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometric analysis of apoptosis
Mechanism Description	Down-regulation of YEATS4 by miR218 sensitizes colorectal cancer cells to L-OHP-induced cell apoptosis by inhibiting cytoprotective autophagy.
Key Molecule: Maternally expressed 3 (MEG3)				[43]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
Cell Pathway Regulation	Cell viability		Activation	hsa05200
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Overexpression of MEG3 improved oxaliplatin sensitivity of HT29/OXA and HCT116/OXA cells via suppressing miR-141 expression and upregulating PDCD4.
Key Molecule: hsa-miR-625-3p				[44]
Resistant Disease	Colorectal adenocarcinoma [ICD-11: 2B91.2]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
	p38/MAPK signaling pathway		Inhibition	hsa04010
In Vitro Model	HEK293 Flp pFRT/eGFP cells	Kidney	Homo sapiens (Human)	CVCL_U427
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	Inactivation of MAP2k6-p38 signalling as one likely mechanism of oxaliplatin resistance, and miR-625-3p induces oxaliplatin resistance by abrogating MAP2k6-p38-regulated apoptosis and cell cycle control networks.
Key Molecule: hsa-mir-520g				[45]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
Cell Pathway Regulation	p53/miR520g/p21 signaling pathway		Regulation	N.A.
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	RkO cells	Colon	Homo sapiens (Human)	CVCL_0504
	FET cells	Colon	Homo sapiens (Human)	CVCL_A604
	GEO cells	Colon	Homo sapiens (Human)	CVCL_0271
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	MTT assay; ELISA assay
Mechanism Description	p53 suppresses miR-520g expression and that deletion of p53 up-regulates miR-520g expression. Inhibition of miR-520g in p53 / cells increased their sensitivity to 5-FU treatment. miR-520g conferred resistance to 5-FU-induced apoptosis through the inhibition of p21 expression, which is a direct target of miR-520g. Rescued expression of p21 in miR-520g-expressing colon cancer cells sensitized them to 5-FU-induced apoptosis. Importantly, experiments in tumor xenograft mouse models demonstrate that miR-520g reduced the effectiveness of 5-FU in the inhibition of tumor growth in vivo. Moreover, studies of colorectal cancer specimens indicate a positive correlation between miR-520g expression and chemoresistance.
Key Molecule: hsa-miR-17-5p				[46]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	PTEN/AKT/PI3K signaling pathway		Activation	hsa05235
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
In Vitro Model	COLO205 cells	Colon	Homo sapiens (Human)	CVCL_F402
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	The expression level of miRNA-17-5p was found increased in chemoresistant patients. Significantly higher expression levels of miR-17-5p were found in CRC patients with distant metastases and higher clinical stages. kaplan-Meier analysis showed that CRC patients with higher levels of miR-17-5p had reduced survival, especially in patients who had previously received chemotherapy. Overexpression of miR-17-5p promoted COLO205 cell invasiveness. PTEN was a target of miR-17-5p in the colon cancer cells, and their context-specific interactions were responsible for multiple drug-resistance. Chemotherapy was found to increase the expression levels of miR-17-5p, which further repressed PTEN levels, contributing to the development of chemo-resistance.
Key Molecule: hsa-mir-19a				[47]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Response evaluation criteria in solid tumors assay
Mechanism Description	Aberrant expression of serum miR-19a in FOLFOX chemotherapy resistance patients, suggesting serum miR-19a could be a potential molecular biomarker for predicting and monitoring resistance to first-line FOLFOX chemotherapy regimens in advanced colorectal cancer patients.
Key Molecule: hsa-mir-203				[16]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	RkO cells	Colon	Homo sapiens (Human)	CVCL_0504
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	We validated ATM as a bona fide target of miR-203 in CRC cells. Mutation of the putative miR-203 binding site in the 3' untranslated region (3'UTR) of the ATM mRNA abolished the inhibitory effect of miR-203 on ATM. Furthermore, stable knockdown of ATM induced resistance to oxaliplatin in chemo-na ve CRC cells.
Key Molecule: hsa-mir-153				[3]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	DLD1 cells	Colon	Homo sapiens (Human)	CVCL_0248
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	CaCo2 cells	Colon	Homo sapiens (Human)	CVCL_0025
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	SW48 cells	Colon	Homo sapiens (Human)	CVCL_1724
	COLO205 cells	Colon	Homo sapiens (Human)	CVCL_F402
In Vivo Model	SCID nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTS assay; Soft agar colony forming ability assay; Flow cytometry assay
Mechanism Description	miR-153 promoted invasiveness indirectly by inducing MMP9 production, whereas drug resistance was mediated directly by inhibiting the Forkhead transcription factor FOXO3a.
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: Aldolase B, fructose-bisphosphate (Aldolase B)				[48]
Metabolic Type	Glucose metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vivo Model	CRC patients			Homo Sapiens
Experiment for Molecule Alteration	Immunohistochemical (IHC) staining
Experiment for Drug Resistance	Overall survival assay (OS)
Mechanism Description	This study has demonstrated that overexpression of ALDOB in CRC cells promotes lactagenesis by regulating PDK1 activation. The secreted lactate is then transported to neighboring cells and converted to pyruvate by lactate-induced LDHB, enhancing the ability of OXPHOS in terms of basal respiration and acting as a repressor of CEACAM6 expression. Consequently, ALDOB/lactate-mediated expression of CEACAM6 promotes cell proliferation and 6-FU chemoresistance in CRC cells.
Key Molecule: Long intergenic non-protein coding RNA 1852 (LINC01852)				[49]
Metabolic Type	Glucose metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	DLD-1 cells	Colon	Homo sapiens (Human)	CVCL_0248
	HCT-116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HCT8 cells	Colon	Homo sapiens (Human)	CVCL_2478
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	RkO cells	Colon	Homo sapiens (Human)	CVCL_0504
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Further mechanistic investigations revealed that LINC01852 increases TRIM72-mediated ubiquitination and degradation of SRSF5, inhibiting SRSF5-mediated alternative splicing of PKM and thereby decreasing the production of PKM2. Overexpression of LINC01852 induces a metabolic switch from aerobic glycolysis to oxidative phosphorylation, which attenuates the chemoresistance of CRC cells by inhibiting PKM2-mediated glycolysis.
Key Molecule: Prostaglandin G/H synthase 2 (Cox-2)				[50]
Metabolic Type	Lipid metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	our findings revealed that oxaliplatin impressed a specific lipid profile signature and lipid transcriptional reprogramming in HT29 cells, which provides new insights into biomarker discovery and pathways for overcoming drug resistance and adverse reactions.
Key Molecule: Inosine monophosphate dehydrogenase 2 (IMPDH2)				[51]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Breast cancer		Activation	hsa05224
	Wnt signaling pathway		Activation	hsa04310
	Adherens junction		Activation	hsa04520
In Vitro Model	HCT8 cells	Colon	Homo sapiens (Human)	CVCL_2478
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Metabolic analysis revealed that the levels of purine metabolites, especially guanosine monophosphate (GMP), were markedly elevated in oxaliplatin-resistant CRC cells. The accumulation of purine metabolites mainly arose from the upregulation of IMPDH2 expression. Gene set enrichment analysis (GSEA) indicated high IMPDH2 expression in CRC correlates with PURINE_METABOLISM and MULTIPLE-DRUG-RESISTANCE pathways. CRC cells with higher IMPDH2 expression were more resistant to oxaliplatin-induced apoptosis.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: Long non-protein coding RNA (CCAL)				[1]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Beta-catenin signaling pathway		Activation	hsa04520
	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	LncRNA CCAL can be transferred from CAFs to cancer cells via exosomes, and exosome-enriched CCAL promoted Oxa and 5-FU chemoresistance of CRC cells.
Key Molecule: hsa-miR-1229-5p				[52]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	PTEN/AKT signaling pathway		Regulation	N.A.
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR-1246, miR-21-5p, miR-96-5p and miR-1229-5p from serum exosomes involved in chemotherapy resistance may be new therapeutic targets, downregulating these miRNAs may promote CRC cell sensitivity to chemotherapeutic drugs.
Key Molecule: hsa-miR-1246				[52]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	PTEN/AKT signaling pathway		Regulation	N.A.
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR-1246, miR-21-5p, miR-96-5p and miR-1229-5p from serum exosomes involved in chemotherapy resistance may be new therapeutic targets, downregulating these miRNAs may promote CRC cell sensitivity to chemotherapeutic drugs.
Key Molecule: hsa-miR-21-5p				[52]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	PTEN/AKT signaling pathway		Regulation	N.A.
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR-1246, miR-21-5p, miR-96-5p and miR-1229-5p from serum exosomes involved in chemotherapy resistance may be new therapeutic targets, downregulating these miRNAs may promote CRC cell sensitivity to chemotherapeutic drugs.
Key Molecule: hsa-miR-96-5p				[52]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	PTEN/AKT signaling pathway		Regulation	N.A.
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR-1246, miR-21-5p, miR-96-5p and miR-1229-5p from serum exosomes involved in chemotherapy resistance may be new therapeutic targets, downregulating these miRNAs may promote CRC cell sensitivity to chemotherapeutic drugs.
Key Molecule: Phosphatase and tensin homolog (PTEN)				[52]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	PTEN/AKT signaling pathway		Regulation	N.A.
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR-1246, miR-21-5p, miR-96-5p and miR-1229-5p from serum exosomes involved in chemotherapy resistance may be new therapeutic targets, downregulating these miRNAs may promote CRC cell sensitivity to chemotherapeutic drugs.
Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1)				[53]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	FHC cells	Colon	Homo sapiens (Human)	CVCL_3688
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Boyden chambers cell migration and invasion assays
Mechanism Description	MALAT1 tethers EZH2 to CDH1 promoter and suppresses miR218 during oxaliplatin treatment, which finally promotes colorectal cancer cell EMT, metastasis, and chemoresistance.
Key Molecule: Cadherin-1 (CDH1)				[53]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	FHC cells	Colon	Homo sapiens (Human)	CVCL_3688
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Boyden chambers cell migration and invasion assays
Mechanism Description	MALAT1 tethers EZH2 to CDH1 promoter and suppresses miR218 during oxaliplatin treatment, which finally promotes colorectal cancer cell EMT, metastasis, and chemoresistance.
Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2)				[53]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	FHC cells	Colon	Homo sapiens (Human)	CVCL_3688
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Boyden chambers cell migration and invasion assays
Mechanism Description	MALAT1 tethers EZH2 to CDH1 promoter and suppresses miR218 during oxaliplatin treatment, which finally promotes colorectal cancer cell EMT, metastasis, and chemoresistance. MALAT1 mediates oxaliplatin-induced EMT through EZH2 and interacts with miR218.
Key Molecule: hsa-mir-141				[54]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Beta-catenin signaling pathway		Regulation	N.A.
	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vivo Model	NOD/SCID mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	CAF-derived exosomes transfer LncRNA H19 to colorectal cancer cells and H19 activated the beta-catenin pathway via acting as a competing endogenous RNA sponge for miR-141, while miR-141 inhibited the stemness of CRC cells.
Key Molecule: H19, imprinted maternally expressed transcript (H19)				[54]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Beta-catenin signaling pathway		Activation	hsa04520
	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vivo Model	NOD/SCID mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	CAF-derived exosomes transfer LncRNA H19 to colorectal cancer cells and H19 activated the beta-catenin pathway via acting as a competing endogenous RNA sponge for miR-141, while miR-141 inhibited the stemness of CRC cells.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Piwi-like protein 2 (PIWIL2)				[39]
Resistant Disease	Colorectal adenocarcinoma [ICD-11: 2B91.2]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
	Cell proliferation		Activation	hsa05200
	STAT3 signaling pathway		Activation	hsa04550
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vitro Model	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis; RT-qPCR
Experiment for Drug Resistance	CCK8 assay; Colony formation assays
Mechanism Description	piR-54265 binds PIWIL2 promotes CRC cell proliferation and invasiveness and 5-FU and oxaliplatin resistance via promoting oncogenic STAT3 signaling.
Key Molecule: T-LAK cell-originated protein kinase(PBK)				[41]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	PI3K/PTEN/AKT signaling pathway		Regulation	N.A.
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	HCT8 cells	Colon	Homo sapiens (Human)	CVCL_2478
	COLO 205 cells	Colon	Homo sapiens (Human)	CVCL_0218
	CCD-18Co cells	Colon	Homo sapiens (Human)	CVCL_2379
	COLO-678 cells	Colon	Homo sapiens (Human)	CVCL_1129
	HT55 cells	Colon	Homo sapiens (Human)	CVCL_1294
	LS1034 cells	Colon	Homo sapiens (Human)	CVCL_1382
	SW1417 cells	Colon	Homo sapiens (Human)	CVCL_1717
	SW403 cells	Colon	Homo sapiens (Human)	CVCL_0545
	SW48 cells	Colon	Homo sapiens (Human)	CVCL_1724
In Vivo Model	BALB/c mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Luciferase activity assay; Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR-216b promotes cell growth and enhances chemosensitivity of colorectal cancer by suppressing PDZ-binding kinase.
Key Molecule: YEATS domain-containing protein 4 (YEATS4)				[42]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HEK293T cells	Kidney	Homo sapiens (Human)	CVCL_0063
	HCT-116/L-OHP cells	Kidney	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometric analysis of apoptosis
Mechanism Description	Down-regulation of YEATS4 by miR218 sensitizes colorectal cancer cells to L-OHP-induced cell apoptosis by inhibiting cytoprotective autophagy.
Key Molecule: Programmed cell death protein 4 (PDCD4)				[43]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
Cell Pathway Regulation	Cell viability		Activation	hsa05200
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	Western blot analysis; Luciferase reporter assay; RNA pull-down assay; RIP assay
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Overexpression of MEG3 improved oxaliplatin sensitivity of HT29/OXA and HCT116/OXA cells via suppressing miR-141 expression and upregulating PDCD4.
Key Molecule: MAPK/ERK kinase 6 (MEK6)				[44]
Resistant Disease	Colorectal adenocarcinoma [ICD-11: 2B91.2]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
	p38/MAPK signaling pathway		Inhibition	hsa04010
In Vitro Model	HEK293 Flp pFRT/eGFP cells	Kidney	Homo sapiens (Human)	CVCL_U427
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	Inactivation of MAP2k6-p38 signalling as one likely mechanism of oxaliplatin resistance, and miR-625-3p induces oxaliplatin resistance by abrogating MAP2k6-p38-regulated apoptosis and cell cycle control networks.
Key Molecule: Ribonuclease P protein subunit p21 (RPP21)				[45]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
Cell Pathway Regulation	p53/miR520g/p21 signaling pathway		Regulation	N.A.
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	RkO cells	Colon	Homo sapiens (Human)	CVCL_0504
	FET cells	Colon	Homo sapiens (Human)	CVCL_A604
	GEO cells	Colon	Homo sapiens (Human)	CVCL_0271
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; ELISA assay
Mechanism Description	p53 suppresses miR-520g expression and that deletion of p53 up-regulates miR-520g expression. Inhibition of miR-520g in p53 / cells increased their sensitivity to 5-FU treatment. miR-520g conferred resistance to 5-FU-induced apoptosis through the inhibition of p21 expression, which is a direct target of miR-520g. Rescued expression of p21 in miR-520g-expressing colon cancer cells sensitized them to 5-FU-induced apoptosis. Importantly, experiments in tumor xenograft mouse models demonstrate that miR-520g reduced the effectiveness of 5-FU in the inhibition of tumor growth in vivo. Moreover, studies of colorectal cancer specimens indicate a positive correlation between miR-520g expression and chemoresistance.
Key Molecule: Phosphatase and tensin homolog (PTEN)				[46]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	PTEN/AKT/PI3K signaling pathway		Activation	hsa05235
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
In Vitro Model	COLO205 cells	Colon	Homo sapiens (Human)	CVCL_F402
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	The expression level of miRNA-17-5p was found increased in chemoresistant patients. Significantly higher expression levels of miR-17-5p were found in CRC patients with distant metastases and higher clinical stages. kaplan-Meier analysis showed that CRC patients with higher levels of miR-17-5p had reduced survival, especially in patients who had previously received chemotherapy. Overexpression of miR-17-5p promoted COLO205 cell invasiveness. PTEN was a target of miR-17-5p in the colon cancer cells, and their context-specific interactions were responsible for multiple drug-resistance. Chemotherapy was found to increase the expression levels of miR-17-5p, which further repressed PTEN levels, contributing to the development of chemo-resistance.
Key Molecule: Serine-protein kinase ATM (ATM)				[16]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	RkO cells	Colon	Homo sapiens (Human)	CVCL_0504
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	We validated ATM as a bona fide target of miR-203 in CRC cells. Mutation of the putative miR-203 binding site in the 3' untranslated region (3'UTR) of the ATM mRNA abolished the inhibitory effect of miR-203 on ATM. Furthermore, stable knockdown of ATM induced resistance to oxaliplatin in chemo-na ve CRC cells.
Key Molecule: Forkhead box protein O3 (FOXO3)				[3]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	DLD1 cells	Colon	Homo sapiens (Human)	CVCL_0248
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	CaCo2 cells	Colon	Homo sapiens (Human)	CVCL_0025
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	SW48 cells	Colon	Homo sapiens (Human)	CVCL_1724
	COLO205 cells	Colon	Homo sapiens (Human)	CVCL_F402
In Vivo Model	SCID nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTS assay; Soft agar colony forming ability assay; Flow cytometry assay
Mechanism Description	miR-153 promoted invasiveness indirectly by inducing MMP9 production, whereas drug resistance was mediated directly by inhibiting the Forkhead transcription factor FOXO3a.
Key Molecule: .				[55]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]			Disease Info
Molecule Alteration	.		.	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Wnt/beta-catenin Signalling Pathway		Regulation	N.A.
In Vitro Model	HCT8 cells	Colon	Homo sapiens (Human)	CVCL_2478
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The results showed that Huaier can regulate autophagy, inhibit the Wnt/-catenin signalling pathway and reverse the drug resistance of OXA-resistant CRC cells.

Kidney cancer [ICD-11: 2C90]

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Metalloproteinase inhibitor 3 (TIMP3)				[21]
Sensitive Disease	Renal carcinoma [ICD-11: 2C90.2]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Kidney cancer [ICD-11: 2C90]
The Specified Disease	Renal carcinoma
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.59E-02 Fold-change: 2.68E+00 Z-score: 3.16E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	PI3K/AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	786-O cells	Kidney	Homo sapiens (Human)	CVCL_1051
	ACHN cells	Pleural effusion	Homo sapiens (Human)	CVCL_1067
	HK-2 cells	Kidney	Homo sapiens (Human)	CVCL_0302
	RCC10 cells	Kidney	Homo sapiens (Human)	CVCL_6265
	RCC4 cells	Kidney	Homo sapiens (Human)	CVCL_0498
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Celltiter96 Aqueous Non Radioactive Cell Proliferation Assay
Mechanism Description	Tumor suppressor genes like PTEN, PDCD4 and TIMP3, are target genes of miR21. PTEN is a potent inhibitor of PI3k/Akt pathway, as well as a direct target of miR21.
Key Molecule: Programmed cell death protein 4 (PDCD4)				[21]
Sensitive Disease	Renal carcinoma [ICD-11: 2C90.2]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Kidney cancer [ICD-11: 2C90]
The Specified Disease	Renal carcinoma
The Studied Tissue	Kidney
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 8.62E-01 Fold-change: 6.66E-03 Z-score: 1.74E-01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	PI3K/AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	786-O cells	Kidney	Homo sapiens (Human)	CVCL_1051
	ACHN cells	Pleural effusion	Homo sapiens (Human)	CVCL_1067
	HK-2 cells	Kidney	Homo sapiens (Human)	CVCL_0302
	RCC10 cells	Kidney	Homo sapiens (Human)	CVCL_6265
	RCC4 cells	Kidney	Homo sapiens (Human)	CVCL_0498
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Celltiter96 Aqueous Non Radioactive Cell Proliferation Assay
Mechanism Description	Tumor suppressor genes like PTEN, PDCD4 and TIMP3, are target genes of miR21. PTEN is a potent inhibitor of PI3k/Akt pathway, as well as a direct target of miR21.

Pancreatic cancer [ICD-11: 2C10]

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: Glucose-6-phosphate dehydrogenase (G6PD)				[13]
Metabolic Type	Glucose metabolism
Resistant Disease	Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Pancreatic cancer [ICD-11: 2C10]
The Specified Disease	Pancreatic ductal adenocarcinoma
The Studied Tissue	Pancreas
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.01E-17 Fold-change: 4.09E-01 Z-score: 9.54E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Adrenergic signaling in cardiomyocytes		Activation	hsa04261
In Vivo Model	HCC patients			Homo Sapiens
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Mechanism Description	Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression.
Key Molecule: Solute carrier family 2 member 1 (SLC2A1)				[13]
Metabolic Type	Glucose metabolism
Resistant Disease	Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Pancreatic cancer [ICD-11: 2C10]
The Specified Disease	Pancreatic ductal adenocarcinoma
The Studied Tissue	Pancreas
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.33E-08 Fold-change: 5.47E-01 Z-score: 5.83E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Adrenergic signaling in cardiomyocytes		Activation	hsa04261
In Vivo Model	HCC patients			Homo Sapiens
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Mechanism Description	Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression.
Key Molecule: Solute carrier family 2 member 1 (SLC2A1)				[13]
Metabolic Type	Glucose metabolism
Resistant Disease	Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Pancreatic cancer [ICD-11: 2C10]
The Specified Disease	Pancreatic cancer
The Studied Tissue	Pancreas
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 4.68E-16 Fold-change: 2.62E-01 Z-score: 1.07E+01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Adrenergic signaling in cardiomyocytes		Activation	hsa04261
In Vivo Model	Female SCID mice of 4-week-old, with fresh tissue from patient			Mice
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Tumor volume assay
Mechanism Description	Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression.
Key Molecule: Glucose-6-phosphate dehydrogenase (G6PD)				[13]
Metabolic Type	Glucose metabolism
Resistant Disease	Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Pancreatic cancer [ICD-11: 2C10]
The Specified Disease	Pancreatic cancer
The Studied Tissue	Pancreas
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.65E-04 Fold-change: 2.06E-01 Z-score: 4.69E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Adrenergic signaling in cardiomyocytes		Activation	hsa04261
In Vivo Model	Female SCID mice of 6-week-old, with fresh tissue from patient			Mice
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Tumor volume assay
Mechanism Description	Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression.
Key Molecule: Aldolase B, fructose-bisphosphate (ALDOB)				[13]
Metabolic Type	Glucose metabolism
Resistant Disease	Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Adrenergic signaling in cardiomyocytes		Activation	hsa04261
In Vivo Model	HCC patients			Homo Sapiens
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Mechanism Description	Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression.
Key Molecule: Aldolase B, fructose-bisphosphate (ALDOB)				[13]
Metabolic Type	Glucose metabolism
Resistant Disease	Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Adrenergic signaling in cardiomyocytes		Activation	hsa04261
In Vivo Model	Female SCID mice of 5-week-old, with fresh tissue from patient			Mice
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Tumor volume assay
Mechanism Description	Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: Microtubule-associated protein 1 light chain 3B II/I (LC3BII/I)				[71]
Resistant Disease	Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MiaPaCa-2 cells	Blood	Homo sapiens (Human)	CVCL_0428
Experiment for Molecule Alteration	Western blot assay; qRT-PCR
Experiment for Drug Resistance	Cell viability assay; Annexin V/PI flow cytometry assay
Mechanism Description	A common characteristic among pancreatic cancer patients is the biomechanically altered tumor microenvironment (TME), which among others is responsible for the elevated mechanical stresses in the tumor interior. Although significant research has elucidated the effect of mechanical stress on cancer cell proliferation and migration, it has not yet been investigated how it could affect cancer cell drug sensitivity. Here, we demonstrated that mechanical stress triggers autophagy activation, correlated with increased resistance to oxaliplatin treatment in pancreatic cancer cells.
Key Molecule: Sequestosome-1				[71]
Resistant Disease	Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MiaPaCa-2 cells	Blood	Homo sapiens (Human)	CVCL_0428
Experiment for Molecule Alteration	Western blot assay; qRT-PCR
Experiment for Drug Resistance	Cell viability assay; Annexin V/PI flow cytometry assay
Mechanism Description	A common characteristic among pancreatic cancer patients is the biomechanically altered tumor microenvironment (TME), which among others is responsible for the elevated mechanical stresses in the tumor interior. Although significant research has elucidated the effect of mechanical stress on cancer cell proliferation and migration, it has not yet been investigated how it could affect cancer cell drug sensitivity. Here, we demonstrated that mechanical stress triggers autophagy activation, correlated with increased resistance to oxaliplatin treatment in pancreatic cancer cells.

Colon cancer [ICD-11: 2B90]

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Insulin receptor substrate 1 (IRS1)				[2]
Resistant Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Colon cancer [ICD-11: 2B90]
The Specified Disease	Colon cancer
The Studied Tissue	Colon tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.83E-01 Fold-change: -1.37E-01 Z-score: -1.08E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Regulation	N.A.
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	293T cells	Breast	Homo sapiens (Human)	CVCL_0063
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	Over-expression of miR-126 in colon cancer cell was able to inhibit cell proliferation, promote cell apoptosis and reduce the invasive ability. miR-126 significantly enhanced the sensitivity of the colon cancer cell to chemotherapeutic drug. It has been shown that IRS1, SLC75A and TOM1 were the potential target genes of miR-126 in colon cancer.
Key Molecule: Ornithine decarboxylase antizyme 2 (OAZ2)				[15]
Resistant Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Colon cancer [ICD-11: 2B90]
The Specified Disease	Colon cancer
The Studied Tissue	Colon tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 8.25E-01 Fold-change: -1.09E-03 Z-score: -2.21E-01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	WST-1 assay; Flow cytometry assay
Mechanism Description	miR-34a positively regulates OAZ2 transcription by directly targeting its 3UTR and OAZ2 Overexpression Effectively Rescues the Chemosensitivity Impaired by miR-34a Deficiency.
Key Molecule: Target of Myb protein 1 (TOM1)				[2]
Resistant Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Colon cancer [ICD-11: 2B90]
The Specified Disease	Colon cancer
The Studied Tissue	Colon tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.36E-14 Fold-change: -4.30E-02 Z-score: -8.19E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	293T cells	Breast	Homo sapiens (Human)	CVCL_0063
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	Over-expression of miR-126 in colon cancer cell was able to inhibit cell proliferation, promote cell apoptosis and reduce the invasive ability. miR-126 significantly enhanced the sensitivity of the colon cancer cell to chemotherapeutic drug. It has been shown that IRS1, SLC75A and TOM1 were the potential target genes of miR-126 in colon cancer.
Key Molecule: Mothers against decapentaplegic homolog 4 (SMAD4)				[25]
Resistant Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Colon cancer [ICD-11: 2B90]
The Specified Disease	Colon cancer
The Studied Tissue	Colon tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.42E-04 Fold-change: -4.75E-02 Z-score: -3.85E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	DLD1 cells	Colon	Homo sapiens (Human)	CVCL_0248
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	CaCo2 cells	Colon	Homo sapiens (Human)	CVCL_0025
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	RkO cells	Colon	Homo sapiens (Human)	CVCL_0504
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	NCM460 cells	Colon	Homo sapiens (Human)	CVCL_0460
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Luciferase reporter assay; Western blot analysis
Experiment for Drug Resistance	Annexin V-PE and 7-AAD double staining method to examine cell viabilityNA; CCK8 assay; Flow cytometric analysis
Mechanism Description	miR19b-3p promotes colon cancer proliferation and oxaliplatin-based chemoresistance by targeting SMAD4.
Key Molecule: Receptor tyrosine-protein kinase erbB-4 (ERBB4)				[23]
Resistant Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	AKT signaling pathway		Activation	hsa04151
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	CaCo2 cells	Colon	Homo sapiens (Human)	CVCL_0025
	NCM460 cells	Colon	Homo sapiens (Human)	CVCL_0460
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Annexin V-APC/PI Apoptosis assay
Mechanism Description	Linc00152 modulates the expression of ERBB4 through competitively binding miR193a-3p. AkT activation mediated by ERBB4 contributes to Linc00152-conferred L-OHP resistance, Linc00152 contributed to L-OHP resistance at least partly through activating AkT pathway.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Cytoskeleton regulator RNA (CYTOR)				[23]
Resistant Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Colon cancer [ICD-11: 2B90]
The Specified Disease	Colon adenocarcinoma
The Studied Tissue	Colon
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 4.65E-55 Fold-change: 1.61E+00 Z-score: 1.82E+01
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	AKT signaling pathway		Activation	hsa04151
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	CaCo2 cells	Colon	Homo sapiens (Human)	CVCL_0025
	NCM460 cells	Colon	Homo sapiens (Human)	CVCL_0460
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	CCK8 assay; Annexin V-APC/PI Apoptosis assay
Mechanism Description	Linc00152 modulates the expression of ERBB4 through competitively binding miR193a-3p. AkT activation mediated by ERBB4 contributes to Linc00152-conferred L-OHP resistance, Linc00152 contributed to L-OHP resistance at least partly through activating AkT pathway.
Key Molecule: hsa-miR-19b-3p				[25]
Resistant Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	DLD1 cells	Colon	Homo sapiens (Human)	CVCL_0248
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	CaCo2 cells	Colon	Homo sapiens (Human)	CVCL_0025
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	RkO cells	Colon	Homo sapiens (Human)	CVCL_0504
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	NCM460 cells	Colon	Homo sapiens (Human)	CVCL_0460
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Annexin V-PE and 7-AAD double staining method to examine cell viabilityNA; CCK8 assay; Flow cytometric analysis
Mechanism Description	miR19b-3p promotes colon cancer proliferation and oxaliplatin-based chemoresistance by targeting SMAD4.
Key Molecule: hsa-mir-34				[15]
Resistant Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	WST-1 assay; Flow cytometry assay
Mechanism Description	miR-34a positively regulates OAZ2 transcription by directly targeting its 3UTR and OAZ2 Overexpression Effectively Rescues the Chemosensitivity Impaired by miR-34a Deficiency.
Key Molecule: hsa-mir-126				[2]
Resistant Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	293T cells	Breast	Homo sapiens (Human)	CVCL_0063
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	Over-expression of miR-126 in colon cancer cell was able to inhibit cell proliferation, promote cell apoptosis and reduce the invasive ability. miR-126 significantly enhanced the sensitivity of the colon cancer cell to chemotherapeutic drug. It has been shown that IRS1, SLC75A and TOM1 were the potential target genes of miR-126 in colon cancer.
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Solute carrier family 7 member 5 (SLC7A5)				[2]
Resistant Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	293T cells	Breast	Homo sapiens (Human)	CVCL_0063
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	Over-expression of miR-126 in colon cancer cell was able to inhibit cell proliferation, promote cell apoptosis and reduce the invasive ability. miR-126 significantly enhanced the sensitivity of the colon cancer cell to chemotherapeutic drug. It has been shown that IRS1, SLC75A and TOM1 were the potential target genes of miR-126 in colon cancer.
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: POU class 2 homeobox 1 (POU2F1)				[34]
Metabolic Type	Glucose metabolism
Resistant Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	HIF-1 signaling pathway		Activation	hsa04066
In Vitro Model	Patients cells	Colon	Homo sapiens (Human)	N.A.
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Apoptosis rate assay
Mechanism Description	Mechanistically, POU2F1 directly bound to the ALDOA promoter to enhance the ALDOA promoter activity in colon cancer cells. Moreover, activation of the POU2F1-ALDOA axis decreased the sensitivity to oxaliplatin in colon cancer cells. These data indicate that the POU2F1-ALDOA axis promotes the progression and oxaliplatin resistance by enhancing metabolic reprogramming in colon cancer.
Key Molecule: Pyruvate kinase muscle isozyme 1 (PKM1)				[14]
Metabolic Type	Mitochondrial metabolism
Resistant Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	DLD-1 cells	Colon	Homo sapiens (Human)	CVCL_0248
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
Experiment for Molecule Alteration	Expression profiles
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.
Key Molecule: POU class 2 homeobox 1 (POU2F1)				[34]
Metabolic Type	Glucose metabolism
Resistant Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	HIF-1 signaling pathway		Activation	hsa04066
In Vivo Model	Male BALB/c nude mice at 4-6 weeks, with SW620 cells			Mice
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Tumor volume assay
Mechanism Description	Mechanistically, POU2F1 directly bound to the ALDOA promoter to enhance the ALDOA promoter activity in colon cancer cells. Moreover, activation of the POU2F1-ALDOA axis decreased the sensitivity to oxaliplatin in colon cancer cells. These data indicate that the POU2F1-ALDOA axis promotes the progression and oxaliplatin resistance by enhancing metabolic reprogramming in colon cancer.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Beclin-1 (BECN1)				[26]
Sensitive Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Colon cancer [ICD-11: 2B90]
The Specified Disease	Colon cancer
The Studied Tissue	Colon tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 6.40E-38 Fold-change: -6.21E-02 Z-score: -1.53E+01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	FHC cells	Colon	Homo sapiens (Human)	CVCL_3688
	DLD1 cells	Colon	Homo sapiens (Human)	CVCL_0248
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	RkO cells	Colon	Homo sapiens (Human)	CVCL_0504
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	CCD-18Co cells	Colon	Homo sapiens (Human)	CVCL_2379
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	The overexpression of miR 409-3p inhibited Beclin-1 expression and autophagic activity by binding to the 3'-untranslated region of Beclin-1 mRNA. In addition, the overexpression of miR 409-3p (+) the chemosensitivity of the oxaliplatin-sensitive and oxaliplatin-resistant colon cancer cells. The restoration of Beclin-1 abrogated these effects of miR 409-3p. In a xenograft model using nude mice, we examined the effects of miR 409-3p on tumor growth during chemotherapy. miR 409-3p overexpression sensitized the tumor to chemotherapy, while inhibiting chemotherapy-induced autophagy in a manner dependent on Beclin-1.
Key Molecule: Y-box-binding protein 1 (YBX1)				[35]
Sensitive Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
In Vitro Model	HCT15 cells	Colon	Homo sapiens (Human)	CVCL_0292
Experiment for Molecule Alteration	Dual luciferase assay; Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	microRNA-137 chemosensitizes colon cancer cells to the chemotherapeutic drug OXA by targeting YBX1, miR137 was involved in repression of YBX1 expression through targeting its 3'-untranslated region. Down-regulation of miR137 conferred OXA resistance in parental cells, while over-expression of miR137 sensitized resistant cells to OXA, which was partly rescued by YBX1 siRNA.
Key Molecule: Sal-like protein 4 (SALL4)				[36]
Sensitive Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	DLD1 cells	Colon	Homo sapiens (Human)	CVCL_0248
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	CaCo2 cells	Colon	Homo sapiens (Human)	CVCL_0025
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	NCM460 cells	Colon	Homo sapiens (Human)	CVCL_0460
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Luciferase assay; Wound healing assay; Transwell assay; Flow cytometry assay
Mechanism Description	The aberrant expression of miR-219-5p and Sall4 in colon cancer specimens, and confirmed that Sall4 was the direct target of miR-219-5p. Additionally, by aid of gain and loss of function assays, miR-219-5p was observed to play an inhibitory effect on cell proliferation, invasion and drug resistance.
Key Molecule: Forkhead box protein M1 (FOXM1)				[37]
Sensitive Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	Wnt/Beta-catenin signaling pathway		Inhibition	hsa04310
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vitro Model	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-320 enhances the sensitivity of human colon cancer cells to chemoradiotherapy in vitro by targeting FOXM1.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-137				[35]
Sensitive Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
In Vitro Model	HCT15 cells	Colon	Homo sapiens (Human)	CVCL_0292
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	microRNA-137 chemosensitizes colon cancer cells to the chemotherapeutic drug OXA by targeting YBX1, miR137 was involved in repression of YBX1 expression through targeting its 3'-untranslated region. Down-regulation of miR137 conferred OXA resistance in parental cells, while over-expression of miR137 sensitized resistant cells to OXA, which was partly rescued by YBX1 siRNA.
Key Molecule: hsa-miR-409-3p				[26]
Sensitive Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	FHC cells	Colon	Homo sapiens (Human)	CVCL_3688
	DLD1 cells	Colon	Homo sapiens (Human)	CVCL_0248
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	RkO cells	Colon	Homo sapiens (Human)	CVCL_0504
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	CCD-18Co cells	Colon	Homo sapiens (Human)	CVCL_2379
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	The overexpression of miR 409-3p inhibited Beclin-1 expression and autophagic activity by binding to the 3'-untranslated region of Beclin-1 mRNA. In addition, the overexpression of miR 409-3p (+) the chemosensitivity of the oxaliplatin-sensitive and oxaliplatin-resistant colon cancer cells. The restoration of Beclin-1 abrogated these effects of miR 409-3p. In a xenograft model using nude mice, we examined the effects of miR 409-3p on tumor growth during chemotherapy. miR 409-3p overexpression sensitized the tumor to chemotherapy, while inhibiting chemotherapy-induced autophagy in a manner dependent on Beclin-1.
Key Molecule: hsa-miR-219a-5p				[36]
Sensitive Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	DLD1 cells	Colon	Homo sapiens (Human)	CVCL_0248
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	CaCo2 cells	Colon	Homo sapiens (Human)	CVCL_0025
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	NCM460 cells	Colon	Homo sapiens (Human)	CVCL_0460
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Luciferase assay; Wound healing assay; Transwell assay; Flow cytometry assay
Mechanism Description	The aberrant expression of miR-219-5p and Sall4 in colon cancer specimens, and confirmed that Sall4 was the direct target of miR-219-5p. Additionally, by aid of gain and loss of function assays, miR-219-5p was observed to play an inhibitory effect on cell proliferation, invasion and drug resistance.
Key Molecule: hsa-mir-320				[37]
Sensitive Disease	Colon cancer [ICD-11: 2B90.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	Wnt/Beta-catenin signaling pathway		Inhibition	hsa04310
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
In Vitro Model	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-320 enhances the sensitivity of human colon cancer cells to chemoradiotherapy in vitro by targeting FOXM1.

Liver cancer [ICD-11: 2C12]

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1)				[22]
Sensitive Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.18E-05 Fold-change: -3.05E-01 Z-score: -4.26E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
	Wnt/Beta-catenin signaling pathway		Inhibition	hsa04310
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	BEL-7402 cells	Liver	Homo sapiens (Human)	CVCL_5492
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	miR-122 inhibits MDR1 expression via suppression of Wnt/beta-catenin pathway, thereby enhancing HCC sensitivity to OXA.

Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Ubiquitin carboxyl-terminal hydrolase 22 (USP22)				[18]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Hepatocellular carcinoma
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.48E-08 Fold-change: 3.19E-01 Z-score: 5.81E+00
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	Hep3B cells	Liver	Homo sapiens (Human)	CVCL_0326
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	PLC cells	Liver	Homo sapiens (Human)	CVCL_0485
	L02 cells	Liver	Homo sapiens (Human)	CVCL_6926
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1)				[6]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Cholangiocarcinoma
The Studied Tissue	Bile duct
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.01E-06 Fold-change: 2.31E+00 Z-score: 5.87E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	Cell viability		Activation	hsa05200
	miR7-5p/ABCC1 signaling pathway		Regulation	N.A.
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	Skhep1 cells	Liver	Homo sapiens (Human)	CVCL_0525
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Overexpression of kCNQ1OT1 enhances OXA resistance through downregulating miR-7-5p and upregulating ABCC1 in HCC cells.
Key Molecule: NR2F1 antisense RNA 1 (NR2F1-AS1)				[24]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver hepatocellular carcinoma
The Studied Tissue	Liver
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.95E-01 Fold-change: 1.56E-01 Z-score: 1.30E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell invasion		Activation	hsa05200
	Cell viability		Activation	hsa05200
	Epithelial mesenchymal transition signaling pathway		Activation	hsa01521
	NR2F1/AS1/miR363/ABCC1 signaling pathway		Regulation	N.A.
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Transwell assay
Mechanism Description	Both NR2F1-AS1 and ABCC1 were up-regulated in oxaliplatin-resistant HCC cells,and miR-363 expression was increased in Huh7/OXA and HepG2/OXA cells transfected with NR2F1-AS1 siRNA compared to empty vector-transfected cells.
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Multidrug resistance-associated protein 1 (MRP1)				[6]
Resistant Disease	Hepatocellular carcinoma [ICD-11: 2C12.2]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Liver cancer [ICD-11: 2C12]
The Specified Disease	Liver cancer
The Studied Tissue	Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 5.12E-23 Fold-change: 1.52E-01 Z-score: 1.09E+01
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
	miR7-5p/ABCC1 signaling pathway		Regulation	N.A.
In Vitro Model	Huh-7 cells	Liver	Homo sapiens (Human)	CVCL_0336
	HepG2 cells	Liver	Homo sapiens (Human)	CVCL_0027
	SMMC7721 cells	Uterus	Homo sapiens (Human)	CVCL_0534
	Skhep1 cells	Liver	Homo sapiens (Human)	CVCL_0525
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Overexpression of kCNQ1OT1 enhances OXA resistance through downregulating miR-7-5p and upregulating ABCC1 in HCC cells.
Aberration of the Drug's Therapeutic Target (ADTT)			Click to Show/Hide
Key Molecule: Dihydroorotate dehydrogenase (DHODH)				[7]
Resistant Disease	Cholangiocarcinoma [ICD-11: 2C12.0]			Disease Info
Molecule Alteration	Missense mutation		Rv0668; p.Arg69Pro	Molecule Info
Experimental Note	Discovered Using In-vivo Testing Model
In Vivo Model	Mouse model			Mus musculus
Experiment for Molecule Alteration	Immunoprecipitation assay; LC-MS/MS analysis
Experiment for Drug Resistance	Cellular ROS and lipid peroxidation level assay; LOXL3 enzymatic assay; In vitro kinase assay
Mechanism Description	To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity.

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: TP53 target 1 (TP53TG1)				[19]
Resistant Disease	Solid tumour/cancer [ICD-11: 2A00-2F9Z]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	p53 signaling pathway		Inhibition	hsa04115
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	MkN-45 cells	Gastric	Homo sapiens (Human)	CVCL_0434
	GCIY cells	Gastric	Homo sapiens (Human)	CVCL_1228
	KATO-3 cells	Gastric	Homo sapiens (Human)	CVCL_0371
	MkN-7 cells	Gastric	Homo sapiens (Human)	CVCL_1417
	SNU-1 cells	Gastric	Homo sapiens (Human)	CVCL_0099
	TGBC11TkB cells	Gastric	Homo sapiens (Human)	CVCL_1768
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
Mechanism Description	TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Y-box-binding protein 1 (YBX1)				[19]
Resistant Disease	Solid tumour/cancer [ICD-11: 2A00-2F9Z]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	p53 signaling pathway		Inhibition	hsa04115
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	MkN-45 cells	Gastric	Homo sapiens (Human)	CVCL_0434
	GCIY cells	Gastric	Homo sapiens (Human)	CVCL_1228
	KATO-3 cells	Gastric	Homo sapiens (Human)	CVCL_0371
	MkN-7 cells	Gastric	Homo sapiens (Human)	CVCL_1417
	SNU-1 cells	Gastric	Homo sapiens (Human)	CVCL_0099
	TGBC11TkB cells	Gastric	Homo sapiens (Human)	CVCL_1768
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
Mechanism Description	TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.

Chronic myeloid leukemia [ICD-11: 2A20]

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: Pyruvate kinase muscle isozyme 1 (PKM1)				[14]
Metabolic Type	Mitochondrial metabolism
Resistant Disease	Chronic myeloid leukemia [ICD-11: 2A20.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	DLD-1 cells	Colon	Homo sapiens (Human)	CVCL_0248
	DLD-1/OxR cells	Blood	Homo sapiens (Human)	CVCL_0248
	K562 cells	Blood	Homo sapiens (Human)	CVCL_0004
Experiment for Molecule Alteration	Expression profiles
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.

Oral squamous cell carcinoma [ICD-11: 2B6E]

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Metabolic Reprogramming via Altered Pathways (MRAP)		Click to Show/Hide
Key Molecule: Histone H3			[11]
Metabolic Type	Glucose metabolism
Resistant Disease	Oral squamous cell carcinoma [ICD-11: 2B6E.0]		Disease Info
Molecule Alteration	Lactylation	.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vivo Model	OSCC samples		Homo Sapiens
Mechanism Description	We found that histone Kla-induced BCAM was overexpressed in OSCC, and a high BCAM level was related to a lower immune cell score and inhibition of immune response. On the other hand, BCAM induced EMT and angiogenesis, leading to OSCC malignant progression via activating the Notch signaling pathway. However, the difference of the BCAM function in Pan-cancers might be attributed to tumor heterogeneity. Taken together, BCAM played a vital role in OSCC chemotherapy resistance and prognosis and contributed to inhibition of the immune process, suggesting that it might be a novel therapeutic target for OSCC.

Esophageal cancer [ICD-11: 2B70]

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-miR-141-3p				[4]
Resistant Disease	Esophageal cancer [ICD-11: 2B70.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	TE-1 cells	Esophagus	Homo sapiens (Human)	CVCL_1759
	EC9706 cells	Esophagus	Homo sapiens (Human)	CVCL_E307
	KYSE150 cells	Esophagus	Homo sapiens (Human)	CVCL_1348
	EC109 cells	Esophagus	Homo sapiens (Human)	CVCL_6898
	EC9706-R cells	Esophagus	Homo sapiens (Human)	CVCL_E307
	Het-1A cells	Esophagus	Homo sapiens (Human)	CVCL_3702
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTT assay; Annexin V-FITC Apoptosis Detection assay
Mechanism Description	Involvement of microRNA-141-3p in 5-fluorouracil and oxaliplatin chemo-resistance in esophageal cancer cells via down-regulation of PTEN.
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Copper-transporting ATPase 1 (ATP7A)				[27]
Resistant Disease	Esophageal squamous cell carcinoma [ICD-11: 2B70.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	EC109 cells	Esophagus	Homo sapiens (Human)	CVCL_6898
Experiment for Molecule Alteration	qRT-PCR; Western blotting assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	Overexpression of ATP7A in EC109/cisplatin cells might increase pumping platinum out of cells or binding and sequestration of platinum drugs, then decrease cellular platinum concentration or keep them away from accessing their key cytotoxic targets in the nucleus, finally result in cisplatin-resistance.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Phosphatase and tensin homolog (PTEN)				[4]
Resistant Disease	Esophageal cancer [ICD-11: 2B70.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	TE-1 cells	Esophagus	Homo sapiens (Human)	CVCL_1759
	EC9706 cells	Esophagus	Homo sapiens (Human)	CVCL_E307
	KYSE150 cells	Esophagus	Homo sapiens (Human)	CVCL_1348
	EC109 cells	Esophagus	Homo sapiens (Human)	CVCL_6898
	EC9706-R cells	Esophagus	Homo sapiens (Human)	CVCL_E307
	Het-1A cells	Esophagus	Homo sapiens (Human)	CVCL_3702
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Annexin V-FITC Apoptosis Detection assay
Mechanism Description	Involvement of microRNA-141-3p in 5-fluorouracil and oxaliplatin chemo-resistance in esophageal cancer cells via down-regulation of PTEN.
Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1)				[10]
Resistant Disease	Oesophagus adenocarcinoma [ICD-11: 2B70.0]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	OE33 cells	Esophagus	Homo sapiens (Human)	CVCL_0471
Experiment for Molecule Alteration	Immunohistochemistry assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.
Key Molecule: Sphingosine kinase 1 (SPHK1)				[10]
Resistant Disease	Oesophagus adenocarcinoma [ICD-11: 2B70.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	OE33 cells	Esophagus	Homo sapiens (Human)	CVCL_0471
Experiment for Molecule Alteration	Immunohistochemistry assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.
Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1)				[10]
Resistant Disease	Esophageal squamous cell carcinoma [ICD-11: 2B70.3]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	OE21 cells	Esophagus	Homo sapiens (Human)	CVCL_2661
Experiment for Molecule Alteration	Immunohistochemistry assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.
Key Molecule: Sphingosine kinase 1 (SPHK1)				[10]
Resistant Disease	Esophageal squamous cell carcinoma [ICD-11: 2B70.3]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	OE21 cells	Esophagus	Homo sapiens (Human)	CVCL_2661
Experiment for Molecule Alteration	Immunohistochemistry assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Oesophagogastric cancer [ICD-11: 2B71]

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)		Click to Show/Hide
Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1)			[10]
Resistant Disease	Gastroesophageal cancer [ICD-11: 2B71.0]		Disease Info
Molecule Alteration	Expression	Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	Gastroesophageal cancer tissue		N.A.
Experiment for Molecule Alteration	Immunohistochemistry assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.
Key Molecule: Sphingosine kinase 1 (SPHK1)			[10]
Resistant Disease	Gastroesophageal cancer [ICD-11: 2B71.0]		Disease Info
Molecule Alteration	Expression	Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	Gastroesophageal cancer tissue		N.A.
Experiment for Molecule Alteration	Immunohistochemistry assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Gastric cancer [ICD-11: 2B72]

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-135a				[5]
Resistant Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Sp1/DAPK2 signaling signaling pathway		Inhibition	hsa05231
In Vitro Model	MGC-803 cells	Gastric	Homo sapiens (Human)	CVCL_5334
	SGC7901 cells	Gastric	Homo sapiens (Human)	CVCL_0520
	NCI-N87 cells	Gastric	Homo sapiens (Human)	CVCL_1603
	MGC-803/OXA cells	Gastric	Homo sapiens (Human)	CVCL_5334
	SGC7901/OXA cells	Gastric	Homo sapiens (Human)	CVCL_B0A1
	SNU-5 cells	Gastric	Homo sapiens (Human)	CVCL_0078
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	miR135a promotes gastric cancer progression and resistance to oxaliplatin. The mechanism whereby miR135a promotes GC pathogenesis appears to be the suppression of E2F1 expression and Sp1/DAPk2 pathway signaling.
Key Molecule: BLACAT1 overlapping LEMD1 locus (BLACAT1)				[28]
Resistant Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	BLACAT1/miR361/ABCB1 signaling pathway		Regulation	N.A.
	Cell apoptosis		Inhibition	hsa04210
	Cell invasion		Activation	hsa05200
	Cell viability		Activation	hsa05200
In Vitro Model	BGC-823 cells	Gastric	Homo sapiens (Human)	CVCL_3360
	MGC-803 cells	Gastric	Homo sapiens (Human)	CVCL_5334
	SGC7901 cells	Gastric	Homo sapiens (Human)	CVCL_0520
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay; Transwell assay
Mechanism Description	BLACAT1 accelerates the oxaliplatin-resistance of gastric cancer via promoting ABCB1 protein expression by targeting miR-361.
Key Molecule: BLACAT1 overlapping LEMD1 locus (BLACAT1)				[28]
Resistant Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell invasion		Activation	hsa05200
	Cell viability		Activation	hsa05200
	miR125a/hexokinase 2 pathway		Regulation	N.A.
In Vitro Model	BGC-823 cells	Gastric	Homo sapiens (Human)	CVCL_3360
	MGC-803 cells	Gastric	Homo sapiens (Human)	CVCL_5334
	SGC7901 cells	Gastric	Homo sapiens (Human)	CVCL_0520
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay; Transwell assay
Mechanism Description	BLACAT1 accelerates the oxaliplatin-resistance of gastric cancer via promoting ABCB1 protein expression by targeting miR-361.
Key Molecule: hsa-mir-361				[28]
Resistant Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	BLACAT1/miR361/ABCB1 signaling pathway		Regulation	N.A.
	Cell apoptosis		Inhibition	hsa04210
	Cell invasion		Activation	hsa05200
	Cell viability		Activation	hsa05200
In Vitro Model	BGC-823 cells	Gastric	Homo sapiens (Human)	CVCL_3360
	MGC-803 cells	Gastric	Homo sapiens (Human)	CVCL_5334
	SGC7901 cells	Gastric	Homo sapiens (Human)	CVCL_0520
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay; Transwell assay
Mechanism Description	BLACAT1 accelerates the oxaliplatin-resistance of gastric cancer via promoting ABCB1 protein expression by targeting miR-361.
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1)				[28]
Resistant Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell invasion		Activation	hsa05200
	Cell viability		Activation	hsa05200
	miR125a/hexokinase 2 pathway		Regulation	N.A.
In Vitro Model	BGC-823 cells	Gastric	Homo sapiens (Human)	CVCL_3360
	MGC-803 cells	Gastric	Homo sapiens (Human)	CVCL_5334
	SGC7901 cells	Gastric	Homo sapiens (Human)	CVCL_0520
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay; Transwell assay
Mechanism Description	BLACAT1 accelerates the oxaliplatin-resistance of gastric cancer via promoting ABCB1 protein expression by targeting miR-361.
Key Molecule: Multidrug resistance protein 1 (ABCB1)				[28]
Resistant Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell invasion		Activation	hsa05200
	Cell viability		Activation	hsa05200
	miR125a/hexokinase 2 pathway		Regulation	N.A.
In Vitro Model	BGC-823 cells	Gastric	Homo sapiens (Human)	CVCL_3360
	MGC-803 cells	Gastric	Homo sapiens (Human)	CVCL_5334
	SGC7901 cells	Gastric	Homo sapiens (Human)	CVCL_0520
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay; Transwell assay
Mechanism Description	BLACAT1 accelerates the oxaliplatin-resistance of gastric cancer via promoting ABCB1 protein expression by targeting miR-361.
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: Dihydroorotate dehydrogenase (DHODH)				[29]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Gastric adenocarcinoma [ICD-11: 2B72.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	AGS cells	Gastric	Homo sapiens (Human)	CVCL_0139
	HGC27 cells	Gastric	Homo sapiens (Human)	CVCL_1279
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	IC50 assay
Mechanism Description	Mechanistically, pyrimidine biosynthesis augmented Notch signaling and transcriptionally increased c-Myc expression, leading to up-regulation of critical glycolytic enzymes. Further studies revealed that pyrimidine synthesis could stabilize gamma-secretase subunit Nicastrin at post-translational N-linked glycosylation level, thereby inducing the cleavage and activation of Notch. Besides, we found that up-regulation of the key enzymes for de novo pyrimidine synthesis CAD and DHODH conferred the chemotherapeutic resistance of gastric cancer via accelerating glycolysis, and pharmacologic inhibition of pyrimidine biosynthetic pathway sensitized cancer cells to chemotherapy in vitro and in vivo.
Key Molecule: Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD)				[29]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Gastric adenocarcinoma [ICD-11: 2B72.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	AGS cells	Gastric	Homo sapiens (Human)	CVCL_0139
	HGC27 cells	Gastric	Homo sapiens (Human)	CVCL_1279
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	IC50 assay
Mechanism Description	Mechanistically, pyrimidine biosynthesis augmented Notch signaling and transcriptionally increased c-Myc expression, leading to up-regulation of critical glycolytic enzymes. Further studies revealed that pyrimidine synthesis could stabilize gamma-secretase subunit Nicastrin at post-translational N-linked glycosylation level, thereby inducing the cleavage and activation of Notch. Besides, we found that up-regulation of the key enzymes for de novo pyrimidine synthesis CAD and DHODH conferred the chemotherapeutic resistance of gastric cancer via accelerating glycolysis, and pharmacologic inhibition of pyrimidine biosynthetic pathway sensitized cancer cells to chemotherapy in vitro and in vivo.
Key Molecule: Pyruvate kinase muscle isozyme 1 (PKM1)				[14]
Metabolic Type	Mitochondrial metabolism
Resistant Disease	Gastric adenocarcinoma [ICD-11: 2B72.0]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MKN45 cells	Liver	Homo sapiens (Human)	CVCL_0434
	NUGC3 cells	Gastric	Homo sapiens (Human)	CVCL_1612
Experiment for Molecule Alteration	Expression profiles
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: Transforming growth factor beta 1 (TGFB1)				[17]
Resistant Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	FAO signaling pathway		Activation	hsa04550
In Vitro Model	AGS cells	Gastric	Homo sapiens (Human)	CVCL_0139
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Enzyme-linked immunosorbent assay
Experiment for Drug Resistance	MTT assay; Colony formation assays
Mechanism Description	Transforming growth factor beta1 (TGF-beta1) secretion by MSCs activated SMAD2/3 through TGF-beta receptors and induced long non-coding RNA (LncRNA) MACC1-AS1 expression in GC cells, which promoted FAO-dependent stemness and chemoresistance through antagonizing miR-145-5p.
Key Molecule: hsa-miR-145-5p				[17]
Resistant Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	FAO signaling pathway		Activation	hsa04550
In Vitro Model	AGS cells	Gastric	Homo sapiens (Human)	CVCL_0139
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Colony formation assays
Mechanism Description	Transforming growth factor beta1 (TGF-beta1) secretion by MSCs activated SMAD2/3 through TGF-beta receptors and induced long non-coding RNA (LncRNA) MACC1-AS1 expression in GC cells, which promoted FAO-dependent stemness and chemoresistance through antagonizing miR-145-5p.
Key Molecule: MACC1 antisense RNA 1 (MACC1-AS1)				[17]
Resistant Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	FAO signaling pathway		Activation	hsa04550
In Vitro Model	AGS cells	Gastric	Homo sapiens (Human)	CVCL_0139
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Colony formation assays
Mechanism Description	Transforming growth factor beta1 (TGF-beta1) secretion by MSCs activated SMAD2/3 through TGF-beta receptors and induced long non-coding RNA (LncRNA) MACC1-AS1 expression in GC cells, which promoted FAO-dependent stemness and chemoresistance through antagonizing miR-145-5p.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Transcription factor E2F1 (E2F1)				[5]
Resistant Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Sp1/DAPK2 signaling signaling pathway		Inhibition	hsa05231
In Vitro Model	MGC-803 cells	Gastric	Homo sapiens (Human)	CVCL_5334
	SGC7901 cells	Gastric	Homo sapiens (Human)	CVCL_0520
	NCI-N87 cells	Gastric	Homo sapiens (Human)	CVCL_1603
	MGC-803/OXA cells	Gastric	Homo sapiens (Human)	CVCL_5334
	SGC7901/OXA cells	Gastric	Homo sapiens (Human)	CVCL_B0A1
	SNU-5 cells	Gastric	Homo sapiens (Human)	CVCL_0078
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	miR135a promotes gastric cancer progression and resistance to oxaliplatin. The mechanism whereby miR135a promotes GC pathogenesis appears to be the suppression of E2F1 expression and Sp1/DAPk2 pathway signaling.
Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1)				[10]
Resistant Disease	Gastric cardia adenocarcinoma [ICD-11: 2B72.2]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	AGS cells	Gastric	Homo sapiens (Human)	CVCL_0139
Experiment for Molecule Alteration	Immunohistochemistry assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.
Key Molecule: Sphingosine kinase 1 (SPHK1)				[10]
Resistant Disease	Gastric cardia adenocarcinoma [ICD-11: 2B72.2]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	AGS cells	Gastric	Homo sapiens (Human)	CVCL_0139
Experiment for Molecule Alteration	Immunohistochemistry assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-miR-195-5p				[30]
Sensitive Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Inhibition	hsa05200
In Vitro Model	MkN28 cells	Gastric	Homo sapiens (Human)	CVCL_1416
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	Overexpression of miR 195 5p inhibit multi drug resistance of gastric cancer cells via downregulating ZNF139.
Key Molecule: Protein lin-28 homolog A (CSDD1)				[31]
Sensitive Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	Lin28/miR107 pathway		Regulation	N.A.
In Vitro Model	MkN-45 cells	Gastric	Homo sapiens (Human)	CVCL_0434
	MkN28 cells	Gastric	Homo sapiens (Human)	CVCL_1416
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Lin28 could inhibit the expression of miR-107, thereby up-regulating C-myc, P-gp and down-regulating Cyclin D1, subsequently result in chemo-resistance of gastric cancer cells. The Lin28/miR-107 pathway might be served as one of many signaling pathways that is associated with gastric cancer chemo-resistance.
Key Molecule: Protein lin-28 homolog B (CSDD2)				[31]
Sensitive Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	Lin28/miR107 pathway		Regulation	N.A.
In Vitro Model	MkN-45 cells	Gastric	Homo sapiens (Human)	CVCL_0434
	MkN28 cells	Gastric	Homo sapiens (Human)	CVCL_1416
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Lin28 could inhibit the expression of miR-107, thereby up-regulating C-myc, P-gp and down-regulating Cyclin D1, subsequently result in chemo-resistance of gastric cancer cells. The Lin28/miR-107 pathway might be served as one of many signaling pathways that is associated with gastric cancer chemo-resistance.
Key Molecule: hsa-miR-107				[31]
Sensitive Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	Lin28/miR107 pathway		Regulation	N.A.
In Vitro Model	MkN-45 cells	Gastric	Homo sapiens (Human)	CVCL_0434
	MkN28 cells	Gastric	Homo sapiens (Human)	CVCL_1416
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Lin28 could inhibit the expression of miR-107, thereby up-regulating C-myc, P-gp and down-regulating Cyclin D1, subsequently result in chemo-resistance of gastric cancer cells. The Lin28/miR-107 pathway might be served as one of many signaling pathways that is associated with gastric cancer chemo-resistance.
Key Molecule: hsa-mir-218				[32]
Sensitive Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
In Vitro Model	SGC7901 cells	Gastric	Homo sapiens (Human)	CVCL_0520
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-218 may inhibit efflux of ADM and oxaliplatin by down-regulating P-gp expression.
Key Molecule: hsa-mir-204				[33]
Sensitive Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
In Vitro Model	NCI-N87 cells	Gastric	Homo sapiens (Human)	CVCL_1603
	GTL-16 cells	Gastric	Homo sapiens (Human)	CVCL_7668
In Vivo Model	CD1 nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	miR-204 targeted Bcl-2 messenger RNA and increased responsiveness of GC cells to 5-fluorouracil and oxaliplatin treatment. Ectopic expression of Bcl-2 protein counteracted miR-204 pro-apoptotic activity in response to 5-fluorouracil.
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: ATP-binding cassette sub-family B5 (ABCB5)				[32]
Sensitive Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
In Vitro Model	SGC7901 cells	Gastric	Homo sapiens (Human)	CVCL_0520
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-218 may inhibit efflux of ADM and oxaliplatin by down-regulating P-gp expression.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Zinc finger protein with KRAB and SCAN domains 1 (ZKSCAN1)				[30]
Sensitive Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Inhibition	hsa05200
In Vitro Model	MkN28 cells	Gastric	Homo sapiens (Human)	CVCL_1416
Experiment for Molecule Alteration	Western blot analysis; RIP assay; Luciferase reporter assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	Overexpression of miR 195 5p inhibit multi drug resistance of gastric cancer cells via downregulating ZNF139.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2)				[32]
Sensitive Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
In Vitro Model	SGC7901 cells	Gastric	Homo sapiens (Human)	CVCL_0520
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	Higher miR-218 levels increased the level of Bax and reduced the level of Bcl-2 and miR-218 inhibits multidrug resistance (MDR) of gastric cancer cells by targeting Hedgehog/smoothened.
Key Molecule: Smoothened homolog (SMO)				[32]
Sensitive Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
In Vitro Model	SGC7901 cells	Gastric	Homo sapiens (Human)	CVCL_0520
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	Higher miR-218 levels increased the level of Bax and reduced the level of Bcl-2 and miR-218 inhibits multidrug resistance (MDR) of gastric cancer cells by targeting Hedgehog/smoothened.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2)				[33]
Sensitive Disease	Gastric cancer [ICD-11: 2B72.1]			Disease Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
In Vitro Model	NCI-N87 cells	Gastric	Homo sapiens (Human)	CVCL_1603
	GTL-16 cells	Gastric	Homo sapiens (Human)	CVCL_7668
In Vivo Model	CD1 nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Immunohistochemistry assay
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	miR-204 targeted Bcl-2 messenger RNA and increased responsiveness of GC cells to 5-fluorouracil and oxaliplatin treatment. Ectopic expression of Bcl-2 protein counteracted miR-204 pro-apoptotic activity in response to 5-fluorouracil.

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Prof. Feng ZHU (zhufeng@zju.edu.cn)