Disease Information

General Information of the Disease (ID: DIS00073)

Name	Colorectal cancer
ICD	ICD-11: 2B91
Resistance Map

Type(s) of Resistant Mechanism of This Disease

ADTT: Aberration of the Drug's Therapeutic Target

DISM: Drug Inactivation by Structure Modification

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 Drug

Approved Drug(s)

15 drug(s) in total

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Fluorouracil

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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: Mast/stem cell growth factor receptor Kit (KIT)				[1]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Fluorouracil			Drug 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 cancer
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 9.75E-30 Fold-change: -3.66E-01 Z-score: -1.26E+01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	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
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	A real-time cell analyzer assay
Mechanism Description	c-KIT was shown to mediate chemo-resistance (kike 5-FU) in ovarian tumor initiating cells, miR-34a inhibits Erk signaling and colony formation by down-regulation of c-kit, miR-34a can inhibit this effect via down-regulation of c-kit and therefore sensitize cells to chemotherapeutic treatment.
Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1)				[2]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Fluorouracil			Drug 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 cancer
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	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	IGF-1R/AKT/S6 signaling pathway		Inhibition	hsa05225
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Ectopic expression of miR-139-5p sensitized CRC cells to 5-FU by increasing 5-FU-induced apoptosis. In addition, miR-139-5p inhibited the expression of the miR-139-5p target gene NOTCH-1 and its downstream molecules MRP-1 and BCL-2, two key MDR-associated genes. Furthermore, silencing NOTCH-1 expression promoted the chemotherapeutic effects of 5-FU, and up-regulation of NOTCH-1 abrogated miR-139-5p-mediated sensitization to 5-FU in LoVo and HCT-116 cells.
Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1)				[4]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]
Sensitive Drug	Fluorouracil			Drug 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
	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: Cadherin-1 (CDH1)				[6]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Colorectal cancer [ICD-11: 2B91]
The Specified Disease	Colorectal cancer
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 8.45E-01 Fold-change: 6.54E-03 Z-score: 1.95E-01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Annexin V/ PI staining; Caspase-3 activity assay
Mechanism Description	Levels of PTEN and E-cadherin were reduced by knockdown of miR200c in HCT-116 cells, PTEN inactivate the AkT signaling pathway, and E-cadherin is one of the major downstream regulators of miRNA-200c contributing to EMT, which is also important to inhibit tumor invasion and proliferation as well as to induce cell apoptosis.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: AT-rich interactive domain-containing protein 4B (ARID4B)				[3]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Fluorouracil			Drug 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 cancer
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.69E-05 Fold-change: -1.63E-01 Z-score: -4.24E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	Cell viability		Inhibition	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	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	CCK8 assay; Flow cytometry assay
Mechanism Description	miR-519b-3p mimics promoted HCT116 and SW480 cells more sensitive to chemoradiation treatment while ectopic expression of ARID4B in the meantime decreased the sensitivity.

Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: HOX transcript antisense RNA (HOTAIR)				[47], [48]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell migration		Inhibition	hsa04670
Cell Pathway Regulation	NF-kB signaling pathway		Activation	hsa04218
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	HOTAIR was associated with EZH2, which subsequently suppressed miR-218 expression, and HOTAIR contributes to 5FU resistance through suppressing miR-218 and activating NF-kB signaling in CRC. Thus, HOTAIR may serve as a promising therapeutic target for CRC patients.
Key Molecule: Long non-protein coding RNA 958 (LINC00958)				[49]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
In Vitro Model	DLD1 cells	Colon	Homo sapiens (Human)	CVCL_0248
In Vitro Model	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay; Colony formation assay
Mechanism Description	BLACAT2 contributes to the cell proliferation, its levels were significantly increased in 5-fluorouracil-resistant cells, and overexpression of BLACAT2 was markedly associated with a low cell inhibition rate.
Key Molecule: hsa-mir-31				[50]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
In Vitro Model	DLD1 cells	Colon	Homo sapiens (Human)	CVCL_0248
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Trypan blue dye-exclusion assay
Mechanism Description	The increased expression level of miR-31 caused 5-FU resistance in colorectal cancer through silencing FIH-1, which is associated with cancer-specific energy metabolism.
Key Molecule: Small nucleolar RNA host gene 15 (SNHG15)				[51]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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
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	BALB/c-Rag2/-IL2cc/immunodeficient mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Flow cytometry assay; Colony formation assay; MTS kit assay
Mechanism Description	The levels of SNHG15 are related with the capacity of CRC cells to cope with the cytotoxic stress caused by 5-FU, which could be mediated by its interaction with AIF.
Key Molecule: GIHCG inhibitor of miR-200b/200a/429 expression (GIHCG)				[52]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
	Cell viability		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				[53]
Resistant Disease	Colorectal adenocarcinoma [ICD-11: 2B91.2]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell metastasis		Activation	hsa05205
	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				[54]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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: CDKN2B antisense RNA 1 (CDKN2B-AS1)				[54]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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	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 regulating the expression of Let-7a in colorectal cancer.
Key Molecule: hsa-mir-218				[48]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell metastasis		Activation	hsa05205
Cell Pathway Regulation	NF-kB signaling pathway		Activation	hsa04218
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
Experiment for Molecule Alteration	qRT-PCR; luciferase reporter assay;ChIP
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	HOTAIR contributes to 5FU resistance through suppressing miR-218 and activating NF-kB signaling in CRC.
Key Molecule: Cytoskeleton regulator RNA (CYTOR)				[55]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell metastasis		Activation	hsa05205
	Cell proliferation		Activation	hsa05200
	Chemoresistance		Activation	hsa05207
	miR139-5p/Notch1 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
	HEK293T cells	Kidney	Homo sapiens (Human)	CVCL_0063
	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	RT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Long non-coding RNA LINC00152 promotes cell proliferation, metastasis, and confers 5-FU resistance in colorectal cancer by inhibiting miR139-5p. LINC00152 could regulate the expression of NOTCH1 through sponging miR139-5p and inhibiting its activity from promoting CRC progression and development.
Key Molecule: hsa-miR-139-5p				[55]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell metastasis		Activation	hsa05205
	Cell proliferation		Activation	hsa05200
	miR139-5p/Notch1 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
	HEK293T cells	Kidney	Homo sapiens (Human)	CVCL_0063
	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	Long non-coding RNA LINC00152 promotes cell proliferation, metastasis, and confers 5-FU resistance in colorectal cancer by inhibiting miR139-5p. LINC00152 could regulate the expression of NOTCH1 through sponging miR139-5p and inhibiting its activity from promoting CRC progression and development.
Key Molecule: Novel transcript, antisense to MYRFL (ENST00000547547)				[56]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	HCT116/5-FU cells	Colon	Homo sapiens (Human)	CVCL_AU09
	LOVO/5-FU cells	Colon	Homo sapiens (Human)	CVCL_0399
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	MTT assay; Flow cytometric analysis
Mechanism Description	Knockdown of miR31 increased the 5-FU sensitivity of CRC cells at least partly by upregulation of apoptosis. Overexpression of ENST00000547547 suppressed the anti-apoptotic effect of miR31 via competitive binding to it. ENST00000547547 reduces the 5-FU resistance via competitive binding to miR31 in CRC cells.
Key Molecule: hsa-mir-31				[56]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Function		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	HCT116/5-FU cells	Colon	Homo sapiens (Human)	CVCL_AU09
	LOVO/5-FU cells	Colon	Homo sapiens (Human)	CVCL_0399
Experiment for Molecule Alteration	RNA immunoprecipitation (RIP) assay; Dual-luciferase reporter assay
Experiment for Drug Resistance	MTT assay; Flow cytometric analysis
Mechanism Description	Knockdown of miR31 increased the 5-FU sensitivity of CRC cells at least partly by upregulation of apoptosis. Overexpression of ENST00000547547 suppressed the anti-apoptotic effect of miR31 via competitive binding to it. ENST00000547547 reduces the 5-FU resistance via competitive binding to miR31 in CRC cells.
Key Molecule: HOX transcript antisense RNA (HOTAIR)				[48]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	NF-kB signaling pathway		Activation	hsa04218
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
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	CCK8 assay; Colony formation assays
Mechanism Description	LncRNA HOTAIR contributes to 5fu resistance through suppressing miR-218 and activating NF-kB/TS signaling in colorectal cancer.
Key Molecule: hsa-mir-218				[48]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	NF-kB signaling pathway		Activation	hsa04218
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
Experiment for Molecule Alteration	qPCR; Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Colony formation assays
Mechanism Description	LncRNA HOTAIR contributes to 5fu resistance through suppressing miR-218 and activating NF-kB/TS signaling in colorectal cancer.
Key Molecule: hsa-mir-135b				[57]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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
	PI3K/AKT signaling pathway		Activation	hsa04151
In Vitro Model	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	HCT-8/5-FU cells	Colon	Homo sapiens (Human)	CVCL_2478
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Upregulation of microRNA-135b and microRNA-182 promotes chemoresistance of colorectal cancer by targeting ST6GALNAC2 via PI3k/AkT pathway. Inhibition of the PI3k/AkT pathway enhanced the chemosensitivity to 5-FU in HCT-8/5-FU and LoVo/5-FU.
Key Molecule: hsa-mir-182				[57]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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
	PI3K/AKT signaling pathway		Activation	hsa04151
In Vitro Model	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	HCT-8/5-FU cells	Colon	Homo sapiens (Human)	CVCL_2478
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Upregulation of microRNA-135b and microRNA-182 promotes chemoresistance of colorectal cancer by targeting ST6GALNAC2 via PI3k/AkT pathway. Inhibition of the PI3k/AkT pathway enhanced the chemosensitivity to 5-FU in HCT-8/5-FU and LoVo/5-FU.
Key Molecule: Sialyltransferase 7B (SIAT7B)				[57]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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
	PI3K/AKT signaling pathway		Activation	hsa04151
In Vitro Model	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	HCT-8/5-FU cells	Colon	Homo sapiens (Human)	CVCL_2478
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Reporter gene assay; RT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Upregulation of microRNA-135b and microRNA-182 promotes chemoresistance of colorectal cancer by targeting ST6GALNAC2 via PI3k/AkT pathway. Inhibition of the PI3k/AkT pathway enhanced the chemosensitivity to 5-FU in HCT-8/5-FU and LoVo/5-FU.
Key Molecule: Long non-protein coding RNA (RP11-708H21.4)				[58]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	AKT/mTOR signaling pathway		Activation	hsa04150
	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	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
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR; Sequencing assay
Experiment for Drug Resistance	CCK8 assay; Colony formation assay
Mechanism Description	Overexpressed RP11-708H21.4 suppresses CRC cell proliferation through inducing G1 arrest. Moreover, up-regulation of RP11-708H21.4 inhibits cell migration and invasion, causes cell apoptosis, and enhances 5-FU sensitivity of CRC cells.
Key Molecule: hsa-mir-106a				[59]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
In Vitro Model	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-106a Reduces 5-Fluorouracil (5-FU) Sensitivity of Colorectal Cancer by downregulating Dual-Specificity Phosphatases 2 (DUSP2).
Key Molecule: Pvt1 oncogene (PVT1)				[60]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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 viability		Activation	hsa05200
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	qPCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	The overexpression of PVT1 increased the mRNA and protein expression levels of multidrug resistance associated protein 1, P glycoprotein, serine/threonine protein kinase mTOR and apoptosis regulator Bcl2.
Key Molecule: Pvt1 oncogene (PVT1)				[60]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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 viability		Activation	hsa05200
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-qPCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	The overexpression of PVT1 increased the mRNA and protein expression levels of multidrug resistance associated protein 1, P glycoprotein, serine/threonine protein kinase mTOR and apoptosis regulator Bcl2.
Key Molecule: hsa-miR-204-5p				[61]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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 proliferation		Activation	hsa05200
	UCA1/miR204-5p ceRNA signaling pathway		Regulation	N.A.
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
	HCT8 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	CCK8 assay
Mechanism Description	LncRNA-UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p.We found that UCA1 was up-regulated in CRCs and negatively correlated with survival time in two CRC cohorts. Further mechanistic studies revealed that UCA1 could sponge endogenous miR-204-5p and inhibit its activity. We also identified CREB1 as a new target of miR-204-5p. The protein levels of CREB1 were significantly up-regulated in CRCs, negatively associated with survival time and positively correlated with the UCA1 expression. The present work provides the first evidence of a UCA1-miR-204-5p-CREB1/BCL2/RAB22A regulatory network in CRC and reveals that UCA1 and CREB1 are potential new oncogenes and prognostic factors for CRC.
Key Molecule: Urothelial cancer associated 1 (UCA1)				[61]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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 proliferation		Activation	hsa05200
	UCA1/miR204-5p ceRNA signaling pathway		Regulation	N.A.
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
	HCT8 cells	Colon	Homo sapiens (Human)	CVCL_2478
Experiment for Molecule Alteration	qRT-PCR; Northern blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	LncRNA-UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p.We found that UCA1 was up-regulated in CRCs and negatively correlated with survival time in two CRC cohorts. Further mechanistic studies revealed that UCA1 could sponge endogenous miR-204-5p and inhibit its activity. We also identified CREB1 as a new target of miR-204-5p. The protein levels of CREB1 were significantly up-regulated in CRCs, negatively associated with survival time and positively correlated with the UCA1 expression. The present work provides the first evidence of a UCA1-miR-204-5p-CREB1/BCL2/RAB22A regulatory network in CRC and reveals that UCA1 and CREB1 are potential new oncogenes and prognostic factors for CRC.
Key Molecule: Urothelial cancer associated 1 (UCA1)				[61]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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 proliferation		Activation	hsa05200
	UCA1/miR204-5p ceRNA signaling pathway		Regulation	N.A.
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
	HCT8 cells	Colon	Homo sapiens (Human)	CVCL_2478
Experiment for Molecule Alteration	qRT-PCR; Northern blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	LncRNA-UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p.We found that UCA1 was up-regulated in CRCs and negatively correlated with survival time in two CRC cohorts. Further mechanistic studies revealed that UCA1 could sponge endogenous miR-204-5p and inhibit its activity. We also identified CREB1 as a new target of miR-204-5p. The protein levels of CREB1 were significantly up-regulated in CRCs, negatively associated with survival time and positively correlated with the UCA1 expression. The present work provides the first evidence of a UCA1-miR-204-5p-CREB1/BCL2/RAB22A regulatory network in CRC and reveals that UCA1 and CREB1 are potential new oncogenes and prognostic factors for CRC.
Key Molecule: hsa-miR-450b-5p				[62]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
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
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-450b-5p inhibited stemness and development of chemoresistance to 5-FU by targeting SOX2 in CRC cells.
Key Molecule: RAC serine/threonine-protein kinase (AKT)				[63]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Phosphorylation		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
Cell Pathway Regulation	miR587/PPP2R1B/pAKT/XIAP signaling pathway		Inhibition	hsa05206
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
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	AkT activation mediated by PPP2R1B contributes to miR-587-conferred 5-FU resistance in colon cancer cells.
Key Molecule: hsa-miR-587				[63]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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	miR587/PPP2R1B/pAKT/XIAP signaling pathway		Inhibition	hsa05206
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	RT-PCR; RT-qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	microRNA-587 antagonizes 5-FU-induced apoptosis and confers drug resistance by inhibiting PPP2R1B expression in colorectal cancer.
Key Molecule: hsa-mir-520g				[64]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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				[65]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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				[66]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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: Bcl-2-like protein 11 (BCL2L11)				[67]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	miR10b/BIM signaling pathway		Activation	hsa05206
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	Luciferase assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-10b directly inhibits pro-apoptotic BIM, and the overexpression of miR-10b confers chemoresistance in colorectal cancer cells to 5-FU.
Key Molecule: hsa-mir-10b				[67]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	miR10b/BIM signaling pathway		Activation	hsa05206
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-10b directly inhibits pro-apoptotic BIM, and the overexpression of miR-10b confers chemoresistance in colorectal cancer cells to 5-FU.
Key Molecule: hsa-mir-21				[68]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
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
	COLO 320DM cells	Colon	Homo sapiens (Human)	CVCL_0219
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	FACS analysis
Mechanism Description	The mismatch repair (MMR) system is involved in DNA damage recognition and repair. Human mutS homolog 2 (hMSH2) and human mutL homolog 1 (hMLH1) function as core MMR proteins and form heterodimers with protein homologs hMSH3 or hMSH6 and hMLH3 or hPMS2, respectively. Colorectal tumors that express a high level of miR-21 display reduced hMSH2 protein expression. Cells that overproduce miR-21 exhibit significantly reduced 5-fluorouracil (5-FU) -induced G2/M damage arrest and apoptosis that is characteristic of defects in the core MMR component.
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Multidrug resistance-associated protein 1 (MRP1)				[54]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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	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: ABC-type oligopeptide transporter ABCB9 (ABCB9)				[56]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell invasion		Activation	hsa05200
Cell Pathway Regulation	Cell migration		Activation	hsa04670
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	HCT116/5-FU cells	Colon	Homo sapiens (Human)	CVCL_AU09
	LOVO/5-FU cells	Colon	Homo sapiens (Human)	CVCL_0399
Experiment for Molecule Alteration	Western blot analysis; qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometric analysis
Mechanism Description	ENST00000547547 promotes ABCB9 expression by acting as a sponge of miR31 and reduces the 5-FU resistance of CRC cells.
Key Molecule: Multidrug resistance-associated protein 1 (MRP1)				[60]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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 viability		Activation	hsa05200
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	CCK8 assay; Flow cytometry assay
Mechanism Description	The overexpression of PVT1 increased the mRNA and protein expression levels of multidrug resistance associated protein 1, P glycoprotein, serine/threonine protein kinase mTOR and apoptosis regulator Bcl2.
Key Molecule: ATP-binding cassette sub-family B5 (ABCB5)				[60]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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 viability		Activation	hsa05200
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	CCK8 assay; Flow cytometry assay
Mechanism Description	The overexpression of PVT1 increased the mRNA and protein expression levels of multidrug resistance associated protein 1, P glycoprotein, serine/threonine protein kinase mTOR and apoptosis regulator Bcl2.
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: Aldolase B, fructose-bisphosphate (Aldolase B)				[69]
Metabolic Type	Glucose metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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 5-FU chemoresistance in CRC cells.
Key Molecule: Dihydroorotate dehydrogenase (DHODH)				[70]
Metabolic Type	Mitochondrial metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vivo Model	Patient-derived organoids			Homo Sapiens
Experiment for Molecule Alteration	MRNA level and western blot analysis
Experiment for Drug Resistance	Tumor volume assay
Mechanism Description	Mechanistically, we report that intracellular lipid accumulation results in lipid peroxidation (LPO) overload, whereas mitochondrial DHODH deficiency weakens the ferroptosis defense system. The combination of these factors makes 5-FU-resistant CRC cells susceptible to ferroptosis. Moreover, mitochondrial DHODH redistribution to the cytosol increases intracellular pyrimidine pools, thereby impeding the effectiveness of 5-FU through molecular competition.
Key Molecule: Long intergenic non-protein coding RNA 1852 (LINC01852)				[71]
Metabolic Type	Glucose metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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: Lactate dehydrogenase A (LDHA)				[72]
Metabolic Type	Glucose metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HCT-116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	SW-480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Mechanistically, METTL3 enhances the expression of LDHA, which catalyzes the conversion of pyruvate to lactate, to trigger glycolysis and 5-FU resistance. METTL3 can increase the transcription of LDHA via stabilizing mRNA of hypoxia-inducible factor (HIF-1alpha), further, METTL3 also triggers the translation of LDHA mRNA via methylation of its CDS region and recruitment of YTH domain-containing family protein 1 (YTHDF1). Targeted inhibition of METTL3/LDHA axis can significantly increase the in vitro and in vivo 5-FU sensitivity of CRC cells.
Key Molecule: Hypoxia-inducible factor 1-alpha (HIF-1alpha)				[73]
Metabolic Type	Glucose metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Longevity regulating pathway - multiple species		Activation	hsa04213
	Breast cancer		Activation	hsa05224
	Wnt signaling pathway		Activation	hsa04310
	Adherens junction		Activation	hsa04520
In Vitro Model	Caco2 cells	Colon	Homo sapiens (Human)	CVCL_0025
	DLD-1 cells	Colon	Homo sapiens (Human)	CVCL_0248
	DiFi cells	Colon	Homo sapiens (Human)	CVCL_6895
	HCT-116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HCT15 cells	Colon	Homo sapiens (Human)	CVCL_0292
	HCT8 cells	Colon	Homo sapiens (Human)	CVCL_2478
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	SW1116 cells	Colon	Homo sapiens (Human)	CVCL_0544
	SW-480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	T84 cells	Colon	Homo sapiens (Human)	CVCL_0555
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Upregulation of HIF-1alpha in 5-FU-resistant CRC occurred through non-oxygen-dependent mechanisms of reactive oxygen species-mediated activation of PI3K/Akt signaling and aberrant activation of beta-catenin in the nucleus. Both HIF-1alpha gene knock-down and pharmacological inhibition restored the sensitivity of CRC to 5-FU.
Key Molecule: Methyltransferase like 3 (METTL3)				[72]
Metabolic Type	Glucose metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HCT-116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	SW-480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Mechanistically, METTL3 enhances the expression of LDHA, which catalyzes the conversion of pyruvate to lactate, to trigger glycolysis and 5-FU resistance. METTL3 can increase the transcription of LDHA via stabilizing mRNA of hypoxia-inducible factor (HIF-1alpha), further, METTL3 also triggers the translation of LDHA mRNA via methylation of its CDS region and recruitment of YTH domain-containing family protein 1 (YTHDF1). Targeted inhibition of METTL3/LDHA axis can significantly increase the in vitro and in vivo 5-FU sensitivity of CRC cells.
Key Molecule: Dihydroorotate dehydrogenase (DHODH)				[70]
Metabolic Type	Mitochondrial metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Caco2 cells	Colon	Homo sapiens (Human)	CVCL_0025
	HCT-116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HCT15 cells	Colon	Homo sapiens (Human)	CVCL_0292
	HCT8 5FU-R cells	Colon	Homo sapiens (Human)	CVCL_2478
	HCT8 cells	Colon	Homo sapiens (Human)	CVCL_2478
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	LoVo 5FU-R cells	Colon	Homo sapiens (Human)	CVCL_0399
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	SW-480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	T84 cells	Colon	Homo sapiens (Human)	CVCL_0555
Experiment for Molecule Alteration	MRNA level and western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Mechanistically, we report that intracellular lipid accumulation results in lipid peroxidation (LPO) overload, whereas mitochondrial DHODH deficiency weakens the ferroptosis defense system. The combination of these factors makes 5-FU-resistant CRC cells susceptible to ferroptosis. Moreover, mitochondrial DHODH redistribution to the cytosol increases intracellular pyrimidine pools, thereby impeding the effectiveness of 5-FU through molecular competition.
Key Molecule: COP9 signalosome subunit 6 (CSN6)				[74]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vivo Model	NU/NU nude mice and C57BL/6 mice, with fresh tissue from patient			Mice
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Tumor volume assay
Mechanism Description	In accordance with these findings, we demonstrated that DDX5 bound to PHGDH mRNA and stimulated its expression by suppressing mRNA degradation in colorectal cancer.
Key Molecule: Dihydroorotate dehydrogenase (DHODH)				[70]
Metabolic Type	Mitochondrial metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vivo Model	Cell line-derived xenograft (CDX) models, 4-week-old male athymic BALB/c nude mice, transplanted with 5-FU-resistant organoid (PDOX5FU-R) ; cell line-derived xenograft (CDX) models, 4-week-old male athymic BALB/c nude mice, transplanted with 5-FU-resistant tumor fragment (PDX5FU-R); cell line-derived xenograft (CDX) models, 4-week-old male athymic BALB/c nude mice, transplanted with HCT8 5FU-R cells (CDXHCT8 5FU-R); cell line-derived xenograft (CDX) models, 4-week-old male athymic BALB/c nude mice, transplanted with HCT8 WT cells (CDXHCT8 WT); patient-derived xenograft (PDX) models, 4-week-old male NOG mice, transplanted with 5-FU-resistant organoid (PDOX5FU-R) ; patient-derived xenograft (PDX) models, 4-week-old male NOG mice, transplanted with 5-FU-resistant tumor fragment (PDX5FU-R); patient-derived xenograft (PDX) models, 4-week-old male NOG mice, transplanted with HCT8 5FU-R cells (CDXHCT8 5FU-R); patient-derived xenograft (PDX) models, 4-week-old male NOG mice, transplanted with HCT8 WT cells (CDXHCT8 WT)			Mice
Experiment for Molecule Alteration	MRNA level and western blot analysis
Experiment for Drug Resistance	Tumor volume assay
Mechanism Description	Mechanistically, we report that intracellular lipid accumulation results in lipid peroxidation (LPO) overload, whereas mitochondrial DHODH deficiency weakens the ferroptosis defense system. The combination of these factors makes 5-FU-resistant CRC cells susceptible to ferroptosis. Moreover, mitochondrial DHODH redistribution to the cytosol increases intracellular pyrimidine pools, thereby impeding the effectiveness of 5-FU through molecular competition.
Key Molecule: L-glutamine amidohydrolase (GLS)				[75]
Metabolic Type	Glutamine metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vivo Model	Four-to-six-week-old female BALB/c mice, with CT26 cells			Mice
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Tumor weight assay
Mechanism Description	In the TME of CRC-PC, tumor cells outcompete adipocytes for Gln, leading to Gln deficiency. We show that this change in the TME induces GS upregulation in adipocytes, increasing the production of Gln, which promotes resistance of tumor cells to 5FU chemotherapy, a process mediated by mTOR activation. We also show that abnormal methionine metabolism in adipocytes may lead to altered H3k4me2 expression, which contributes to GS upregulation and chemoresistance to 5FU
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: Long non-protein coding RNA (CCAL)				[76]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fluorouracil			Drug 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.

Drug resistance Data Categorized by Their Corresponding Mechanisms
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: Dihydroorotate dehydrogenase (DHODH)				[70]
Metabolic Type	Mitochondrial metabolism
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Fluorouracil			Drug 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	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 10-FU metabolite concentrations
Key Molecule: Dihydroorotate dehydrogenase (DHODH)				[70]
Metabolic Type	Mitochondrial metabolism
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Caco2 cells	Colon	Homo sapiens (Human)	CVCL_0025
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 11-FU metabolite concentrations
Key Molecule: Dihydroorotate dehydrogenase (DHODH)				[70]
Metabolic Type	Mitochondrial metabolism
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	T84 cells	Colon	Homo sapiens (Human)	CVCL_0555
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 12-FU metabolite concentrations
Key Molecule: Dihydroorotate dehydrogenase (DHODH)				[70]
Metabolic Type	Mitochondrial metabolism
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HCT8 cells	Colon	Homo sapiens (Human)	CVCL_2478
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 5-FU metabolite concentrations
Key Molecule: Dihydroorotate dehydrogenase (DHODH)				[70]
Metabolic Type	Mitochondrial metabolism
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HCT15 cells	Colon	Homo sapiens (Human)	CVCL_0292
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 6-FU metabolite concentrations
Key Molecule: Dihydroorotate dehydrogenase (DHODH)				[70]
Metabolic Type	Mitochondrial metabolism
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HCT-116 cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 7-FU metabolite concentrations
Key Molecule: Dihydroorotate dehydrogenase (DHODH)				[70]
Metabolic Type	Mitochondrial metabolism
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 8-FU metabolite concentrations
Key Molecule: Dihydroorotate dehydrogenase (DHODH)				[70]
Metabolic Type	Mitochondrial metabolism
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Fluorouracil			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	SW-480 cells	Colon	Homo sapiens (Human)	CVCL_0546
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 9-FU metabolite concentrations

Vincristine

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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)				[4]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]
Sensitive Drug	Vincristine			Drug 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
	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.

Oxaliplatin

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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)				[4]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]
Sensitive Drug	Oxaliplatin			Drug 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
	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.

Berberine

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Cancer susceptibility 2 (CASC2)				[8]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Berberine			Drug 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
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	LncRNA CASC2 mediates the berberine-induced pro-apoptotic effect via inhibition of Bcl-2 expression at the post-transcriptional level.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Apoptosis regulator Bcl-2 (BCL2)				[8]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Berberine			Drug 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
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	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	LncRNA CASC2 mediates the berberine-induced pro-apoptotic effect via inhibition of Bcl-2 expression at the post-transcriptional level.

Bevacizumab

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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				[9]
Metabolic Type	Glucose metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Bevacizumab			Drug Info
Molecule Alteration	Lactylation		H3K18la	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HCT-116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.
Key Molecule: Enolase 2 (ENO2)				[10]
Metabolic Type	Glucose metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Bevacizumab			Drug 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
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
In Vivo Model	6-to 8-week-old female NOD/SCID mice, with fresh tissue from patient			Mice
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Here, we found that high levels of ENO2 expression and ENO2-related neuroendocrine differentiation were associated with resistance to antiangiogenic therapy in CRC. Notably, the ENO2-derived PEP was responsible for ENO2-mediated resistance to antiangiogenic therapy in CRC, and PEP enhanced beta-catenin Lys49 acetylation by selectively inhibiting histone deacetylase 1 (HDAC1) activity.
Key Molecule: Enolase 2 (ENO2)				[10]
Metabolic Type	Glucose metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Bevacizumab			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HCT-116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
In Vivo Model	4-to 6-week-old female BALB/c nude mice, with HCT116vector, HCT116ENO2, HCT116shNC and HCT116shENO2, Rego-resistant SW620 or Bev-resistant HCT116 cells			Mice
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Here, we found that high levels of ENO2 expression and ENO2-related neuroendocrine differentiation were associated with resistance to antiangiogenic therapy in CRC. Notably, the ENO2-derived PEP was responsible for ENO2-mediated resistance to antiangiogenic therapy in CRC, and PEP enhanced beta-catenin Lys49 acetylation by selectively inhibiting histone deacetylase 1 (HDAC1) activity.
Key Molecule: Histone H3				[9]
Metabolic Type	Glucose metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Bevacizumab			Drug Info
Molecule Alteration	Lactylation		H3K18la	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vivo Model	Patient-derived xenograft (PDX) mice			Mice
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Quantification viability of patient-derived organoids
Mechanism Description	Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.
Key Molecule: Histone H3				[9]
Metabolic Type	Glucose metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Bevacizumab			Drug Info
Molecule Alteration	Lactylation		H3K18la	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vivo Model	Patient-derived xenograft (PDX) mice			Mice
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Tumor weight assay
Mechanism Description	Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.
Key Molecule: Histone H3				[9]
Metabolic Type	Glucose metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Bevacizumab			Drug Info
Molecule Alteration	Lactylation		H3K18la	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HCT-116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Western blot assay
Mechanism Description	Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.

Cabozantinib

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: VEGF-2 receptor (KDR)				[11]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Cabozantinib			Drug Info
Molecule Alteration	Missense mutation		p.R1032Q (c.3095G>A)	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	VEGF signaling pathway		Activation	hsa04370
In Vitro Model	Colo-320 cells	Colon	Homo sapiens (Human)	CVCL_1989
	MDST8 cells	Colon	Homo sapiens (Human)	CVCL_2588
In Vivo Model	Nude mouse PDX model			Mus musculus
Experiment for Molecule Alteration	BEAMing assay; Western blot analysis; immunofluorescence assay
Experiment for Drug Resistance	Promega assay
Mechanism Description	VEGFR2 is somatically mutated across tumor types and that VEGFR2 mutants can be oncogenic and control sensitivity/resistance to antiangiogenic drugs.

Cetuximab

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Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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Key Molecule: Epidermal growth factor receptor (EGFR)

[12]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Missense mutation

p.G465E

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vitro Model

Colon cells

Colon

Homo sapiens (Human)

N.A.

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Next-generation sequencing assay

Experiment for
Drug Resistance

Liquid biopsy assay

Mechanism Description

Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

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Key Molecule: POU class 5 homeobox 1 pseudogene 4 (POU5F1P4)

[13]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vitro Model

CaCo2 cells

Colon

Homo sapiens (Human)

CVCL_0025

NCI-H508 cells

Colon

Homo sapiens (Human)

CVCL_1564

Experiment for
Molecule Alteration

qPCR

Experiment for
Drug Resistance

CCK8 assay

Mechanism Description

Down-regulation of POU5F1P4 decreased the sensitivity of colorectal cancer cells to cetuximab. POU5F1P4 may contribute to cetuximab resistance by interacting with protein coding genes that affect different biological pathways.

Key Molecule: Mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG)

[14]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Wnt/Beta-catenin signaling pathway

Inhibition

hsa04310

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

RkO cells

Colon

Homo sapiens (Human)

CVCL_0504

HCT8 cells

Colon

Homo sapiens (Human)

CVCL_2478

NCI-H508 cells

Colon

Homo sapiens (Human)

CVCL_1564

SW1116 cells

Colon

Homo sapiens (Human)

CVCL_0544

COLO 320DM cells

Colon

Homo sapiens (Human)

CVCL_0219

HCT15 cells

Colon

Homo sapiens (Human)

CVCL_0292

LS174T cells

Colon

Homo sapiens (Human)

CVCL_1384

NCI-H716 cells

Colon

Homo sapiens (Human)

CVCL_1581

SW948 cells

Colon

Homo sapiens (Human)

CVCL_0632

SW403 cells

Colon

Homo sapiens (Human)

CVCL_0545

SW48 cells

Colon

Homo sapiens (Human)

CVCL_1724

COLO205 cells

Colon

Homo sapiens (Human)

CVCL_F402

HuTu80 cells

Small intestine

Homo sapiens (Human)

CVCL_1301

LS123 cells

Colon

Homo sapiens (Human)

CVCL_1383

SK-CO-1 cells

Colon

Homo sapiens (Human)

CVCL_0626

SW837 cells

Colon

Homo sapiens (Human)

CVCL_1729

T84 cells

Colon

Homo sapiens (Human)

CVCL_0555

In Vivo Model

Nude mouse xenograft model

Mus musculus

Experiment for
Molecule Alteration

qPCR; Sequencing assay

Experiment for
Drug Resistance

CCK8 assay

Mechanism Description

There is a double-negative feedback loop between MIR100HG and the transcription factor GATA6, whereby GATA6 represses MIR100HG, but this repression is relieved by miR125b targeting of GATA6.

Key Molecule: hsa-mir-100

[14]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Wnt/Beta-catenin signaling pathway

Inhibition

hsa04310

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

RkO cells

Colon

Homo sapiens (Human)

CVCL_0504

HCT8 cells

Colon

Homo sapiens (Human)

CVCL_2478

NCI-H508 cells

Colon

Homo sapiens (Human)

CVCL_1564

SW1116 cells

Colon

Homo sapiens (Human)

CVCL_0544

COLO 320DM cells

Colon

Homo sapiens (Human)

CVCL_0219

HCT15 cells

Colon

Homo sapiens (Human)

CVCL_0292

LS174T cells

Colon

Homo sapiens (Human)

CVCL_1384

NCI-H716 cells

Colon

Homo sapiens (Human)

CVCL_1581

SW948 cells

Colon

Homo sapiens (Human)

CVCL_0632

SW403 cells

Colon

Homo sapiens (Human)

CVCL_0545

SW48 cells

Colon

Homo sapiens (Human)

CVCL_1724

COLO205 cells

Colon

Homo sapiens (Human)

CVCL_F402

HuTu80 cells

Small intestine

Homo sapiens (Human)

CVCL_1301

LS123 cells

Colon

Homo sapiens (Human)

CVCL_1383

SK-CO-1 cells

Colon

Homo sapiens (Human)

CVCL_0626

SW837 cells

Colon

Homo sapiens (Human)

CVCL_1729

T84 cells

Colon

Homo sapiens (Human)

CVCL_0555

In Vivo Model

Nude mouse xenograft model

Mus musculus

Experiment for
Molecule Alteration

Luciferase reporter assay; qRT-PCR

Experiment for
Drug Resistance

CCK8 assay

Mechanism Description

miR100 and miR125b coordinately repressed five Wnt/beta-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness.

Key Molecule: hsa-mir-125b

[14]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Wnt/Beta-catenin signaling pathway

Inhibition

hsa04310

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

RkO cells

Colon

Homo sapiens (Human)

CVCL_0504

HCT8 cells

Colon

Homo sapiens (Human)

CVCL_2478

NCI-H508 cells

Colon

Homo sapiens (Human)

CVCL_1564

SW1116 cells

Colon

Homo sapiens (Human)

CVCL_0544

COLO 320DM cells

Colon

Homo sapiens (Human)

CVCL_0219

HCT15 cells

Colon

Homo sapiens (Human)

CVCL_0292

LS174T cells

Colon

Homo sapiens (Human)

CVCL_1384

NCI-H716 cells

Colon

Homo sapiens (Human)

CVCL_1581

SW948 cells

Colon

Homo sapiens (Human)

CVCL_0632

SW403 cells

Colon

Homo sapiens (Human)

CVCL_0545

SW48 cells

Colon

Homo sapiens (Human)

CVCL_1724

COLO205 cells

Colon

Homo sapiens (Human)

CVCL_F402

HuTu80 cells

Small intestine

Homo sapiens (Human)

CVCL_1301

LS123 cells

Colon

Homo sapiens (Human)

CVCL_1383

SK-CO-1 cells

Colon

Homo sapiens (Human)

CVCL_0626

SW837 cells

Colon

Homo sapiens (Human)

CVCL_1729

T84 cells

Colon

Homo sapiens (Human)

CVCL_0555

In Vivo Model

Nude mouse xenograft model

Mus musculus

Experiment for
Molecule Alteration

Luciferase reporter assay; qRT-PCR

Experiment for
Drug Resistance

CCK8 assay

Mechanism Description

Key Molecule: Mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG)

[14]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

Wnt/Beta-catenin signaling pathway

Activation

hsa04310

In Vitro Model

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

GIST-T1 cells

Gastric

Homo sapiens (Human)

CVCL_4976

CAL62 cells

Thyroid gland

Homo sapiens (Human)

CVCL_1112

CAL-62 cells

Thyroid gland

Homo sapiens (Human)

CVCL_1112

CCL-131 cells

Brain

Mus musculus (Mouse)

CVCL_0470

COLO320DM cells

Colon

Homo sapiens (Human)

CVCL_0219

CT26 WT cells

Colon

Mus musculus (Mouse)

CVCL_7256

Detroit562 cells

Pleural effusion

Homo sapiens (Human)

CVCL_1171

DIPG 007 cells

Brain

Homo sapiens (Human)

CVCL_VU70

DLD-1 cells

Colon

Homo sapiens (Human)

CVCL_0248

DU145 cells

Prostate

Homo sapiens (Human)

CVCL_0105

FL83B cells

Liver

Mus musculus (Mouse)

CVCL_4691

GH3 cells

Pituitary gland

Rattus norvegicus (Rat)

CVCL_0273

GH4C1 cells

pituitary gland

Rattus norvegicus (Rat)

CVCL_0276

H1650 cells

Pleural effusion

Homo sapiens (Human)

CVCL_4V01

H9 cells

Peripheral blood

Homo sapiens (Human)

CVCL_1240

H9/HTLV cells

Peripheral blood

Homo sapiens (Human)

CVCL_3514

HEK 293T cells

Kidney

Homo sapiens (Human)

CVCL_0063

HeLa S cells

Uterus

Homo sapiens (Human)

CVCL_0058

HeLa229 cells

Uterus

Homo sapiens (Human)

CVCL_1276

HH cells

Peripheral blood

Homo sapiens (Human)

CVCL_1280

HPrEC cells

Prostate

Homo sapiens (Human)

CVCL_A2EM

Human RPMI8226 myeloma cells

Peripheral blood

Homo sapiens (Human)

CVCL_0014

KB-C2 cells

Uterus

Homo sapiens (Human)

CVCL_D600

Experiment for
Molecule Alteration

RT-PCR

Mechanism Description

miR-100HG, miR-100 and miR-125b overexpression was also observed in cetuximab-resistant colorectal cancer and head and neck squamous cell cancer cell lines and in tumors from colorectal cancer patients that progressed on cetuximab. miR-100 and miR-125b coordinately repressed five Wnt/beta-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness.

Key Molecule: hsa-mir-100

[14]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

Wnt/Beta-catenin signaling pathway

Activation

hsa04310

In Vitro Model

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

GIST-T1 cells

Gastric

Homo sapiens (Human)

CVCL_4976

CAL62 cells

Thyroid gland

Homo sapiens (Human)

CVCL_1112

CAL-62 cells

Thyroid gland

Homo sapiens (Human)

CVCL_1112

CCL-131 cells

Brain

Mus musculus (Mouse)

CVCL_0470

COLO320DM cells

Colon

Homo sapiens (Human)

CVCL_0219

CT26 WT cells

Colon

Mus musculus (Mouse)

CVCL_7256

Detroit562 cells

Pleural effusion

Homo sapiens (Human)

CVCL_1171

DIPG 007 cells

Brain

Homo sapiens (Human)

CVCL_VU70

DLD-1 cells

Colon

Homo sapiens (Human)

CVCL_0248

DU145 cells

Prostate

Homo sapiens (Human)

CVCL_0105

FL83B cells

Liver

Mus musculus (Mouse)

CVCL_4691

GH3 cells

Pituitary gland

Rattus norvegicus (Rat)

CVCL_0273

GH4C1 cells

pituitary gland

Rattus norvegicus (Rat)

CVCL_0276

H1650 cells

Pleural effusion

Homo sapiens (Human)

CVCL_4V01

H9 cells

Peripheral blood

Homo sapiens (Human)

CVCL_1240

H9/HTLV cells

Peripheral blood

Homo sapiens (Human)

CVCL_3514

HEK 293T cells

Kidney

Homo sapiens (Human)

CVCL_0063

HeLa S cells

Uterus

Homo sapiens (Human)

CVCL_0058

HeLa229 cells

Uterus

Homo sapiens (Human)

CVCL_1276

HH cells

Peripheral blood

Homo sapiens (Human)

CVCL_1280

HPrEC cells

Prostate

Homo sapiens (Human)

CVCL_A2EM

Human RPMI8226 myeloma cells

Peripheral blood

Homo sapiens (Human)

CVCL_0014

KB-C2 cells

Uterus

Homo sapiens (Human)

CVCL_D600

Experiment for
Molecule Alteration

RT-PCR

Mechanism Description

Key Molecule: hsa-mir-125b

[14]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

Wnt/Beta-catenin signaling pathway

Activation

hsa04310

In Vitro Model

MDA-MB-231 cells

Breast

Homo sapiens (Human)

CVCL_0062

GIST-T1 cells

Gastric

Homo sapiens (Human)

CVCL_4976

CAL62 cells

Thyroid gland

Homo sapiens (Human)

CVCL_1112

CAL-62 cells

Thyroid gland

Homo sapiens (Human)

CVCL_1112

CCL-131 cells

Brain

Mus musculus (Mouse)

CVCL_0470

COLO320DM cells

Colon

Homo sapiens (Human)

CVCL_0219

CT26 WT cells

Colon

Mus musculus (Mouse)

CVCL_7256

Detroit562 cells

Pleural effusion

Homo sapiens (Human)

CVCL_1171

DIPG 007 cells

Brain

Homo sapiens (Human)

CVCL_VU70

DLD-1 cells

Colon

Homo sapiens (Human)

CVCL_0248

DU145 cells

Prostate

Homo sapiens (Human)

CVCL_0105

FL83B cells

Liver

Mus musculus (Mouse)

CVCL_4691

GH3 cells

Pituitary gland

Rattus norvegicus (Rat)

CVCL_0273

GH4C1 cells

pituitary gland

Rattus norvegicus (Rat)

CVCL_0276

H1650 cells

Pleural effusion

Homo sapiens (Human)

CVCL_4V01

H9 cells

Peripheral blood

Homo sapiens (Human)

CVCL_1240

H9/HTLV cells

Peripheral blood

Homo sapiens (Human)

CVCL_3514

HEK 293T cells

Kidney

Homo sapiens (Human)

CVCL_0063

HeLa S cells

Uterus

Homo sapiens (Human)

CVCL_0058

HeLa229 cells

Uterus

Homo sapiens (Human)

CVCL_1276

HH cells

Peripheral blood

Homo sapiens (Human)

CVCL_1280

HPrEC cells

Prostate

Homo sapiens (Human)

CVCL_A2EM

Human RPMI8226 myeloma cells

Peripheral blood

Homo sapiens (Human)

CVCL_0014

KB-C2 cells

Uterus

Homo sapiens (Human)

CVCL_D600

Experiment for
Molecule Alteration

RT-PCR

Mechanism Description

Metabolic Reprogramming via Altered Pathways (MRAP)

Click to Show/Hide

Key Molecule: Solute carrier family 25 member 21 (SLC25A21)

[15]

Metabolic Type

Glutamine metabolism

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

Caco2 cells

Colon

Homo sapiens (Human)

CVCL_0025

DLD-1 cells

Colon

Homo sapiens (Human)

CVCL_0248

HT-29 cells

Colon

Homo sapiens (Human)

CVCL_0320

LS 174T cells

Colon

Homo sapiens (Human)

CVCL_1384

LOVO cells

Colon

Homo sapiens (Human)

CVCL_0399

Experiment for
Molecule Alteration

qRT-PCR; Western blot analysis

Experiment for
Drug Resistance

Cell viability assay

Mechanism Description

Restoration of SLC25A21 expression abrogates KRAS-mutation-mediated resistance to cetuximab in CRC. KRAS mutation, which results in hyperactive PI3K/AKT and RAF/ERK signaling (26), is responsible for resistance to anti-EGFR antibody therapy (27).

Key Molecule: Solute carrier family 25 member 21 (SLC25A21)

[15]

Metabolic Type

Glutamine metabolism

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

In Vitro Model

M5 cells

Colon

Homo sapiens (Human)

CVCL_WH33

SW620 cells

Colon

Homo sapiens (Human)

CVCL_0547

Experiment for
Molecule Alteration

qRT-PCR; Western blot analysis

Experiment for
Drug Resistance

Cell viability assay

Mechanism Description

Regulation by the Disease Microenvironment (RTDM)

Click to Show/Hide

Key Molecule: Programmed cell death 6-interacting protein (PDCD6IP)

[16]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

Cell colony

Activation

hsa05200

Cell invasion

Activation

hsa05200

Cell migration

Activation

hsa04670

Cell proliferation

Activation

hsa05200

In Vitro Model

CaCo2 cells

Colon

Homo sapiens (Human)

CVCL_0025

Experiment for
Molecule Alteration

Western blot analysis

Experiment for
Drug Resistance

CCK8 assay; Flow cytometry assay

Mechanism Description

UCA1 expression was markedly higher in cetuximab-resistant cancer cells and their exosomes and the expression of TSG101, Alix, and CD81, which are all exosome markers and are associated with exosome formation, in both exosomes and cells.

Key Molecule: Urothelial cancer associated 1 (UCA1)

[16]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

Cell apoptosis

Inhibition

hsa04210

Cell colony

Activation

hsa05200

Cell proliferation

Activation

hsa05200

In Vitro Model

CaCo2 cells

Colon

Homo sapiens (Human)

CVCL_0025

Experiment for
Molecule Alteration

qRT-PCR

Experiment for
Drug Resistance

CCK8 assay; Flow cytometry assay

Mechanism Description

Key Molecule: GDH/6PGL endoplasmic bifunctional protein (H6PD)

[17]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Discovered Using In-vivo Testing Model

Cell Pathway Regulation

Pentose phosphate signaling pathway

Activation

hsa00030

In Vitro Model

SW480 cells

Colon

Homo sapiens (Human)

CVCL_0546

GEO cells

Colon

Homo sapiens (Human)

CVCL_0271

In Vivo Model

Xenografts mouse model

Mus musculus

Experiment for
Molecule Alteration

2D DIGE assay

Mechanism Description

LDHB and PDHA1 were downregulated in GEO-CR tumor xenografts, similarly to the corresponding deregulations observed in the derived cell lines. Upregulation of G6PDH and transketolase (TkT) was also actually maintained in tumor xenografts. Indeed, PPP2CA expression in xenografted samples was similarly evaluated, demonstrating that protein downregulation in vivo was even more pronounced than that measured in GEO-CR cells.

Key Molecule: L-lactate dehydrogenase B chain (LDHB)

[17]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Discovered Using In-vivo Testing Model

Cell Pathway Regulation

Pentose phosphate signaling pathway

Activation

hsa00030

In Vitro Model

SW480 cells

Colon

Homo sapiens (Human)

CVCL_0546

GEO cells

Colon

Homo sapiens (Human)

CVCL_0271

In Vivo Model

Xenografts mouse model

Mus musculus

Experiment for
Molecule Alteration

2D DIGE assay

Mechanism Description

Key Molecule: Pyruvate dehydrogenase E1 component subunit alpha (PDHA1)

[17]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Discovered Using In-vivo Testing Model

Cell Pathway Regulation

Pentose phosphate signaling pathway

Activation

hsa00030

In Vitro Model

SW480 cells

Colon

Homo sapiens (Human)

CVCL_0546

GEO cells

Colon

Homo sapiens (Human)

CVCL_0271

In Vivo Model

Xenografts mouse model

Mus musculus

Experiment for
Molecule Alteration

2D DIGE assay

Mechanism Description

Key Molecule: Transketolase (TKT)

[17]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Discovered Using In-vivo Testing Model

Cell Pathway Regulation

Pentose phosphate signaling pathway

Activation

hsa00030

In Vitro Model

SW480 cells

Colon

Homo sapiens (Human)

CVCL_0546

GEO cells

Colon

Homo sapiens (Human)

CVCL_0271

In Vivo Model

Xenografts mouse model

Mus musculus

Experiment for
Molecule Alteration

2D DIGE assay

Mechanism Description

Unusual Activation of Pro-survival Pathway (UAPP)

Click to Show/Hide

Key Molecule: Transcription factor GATA6 (GATA6)

[14]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

Chemoresistance

Activation

hsa05207

Wnt/Beta-catenin signaling pathway

Inhibition

hsa04310

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

RkO cells

Colon

Homo sapiens (Human)

CVCL_0504

HCT8 cells

Colon

Homo sapiens (Human)

CVCL_2478

NCI-H508 cells

Colon

Homo sapiens (Human)

CVCL_1564

SW1116 cells

Colon

Homo sapiens (Human)

CVCL_0544

COLO 320DM cells

Colon

Homo sapiens (Human)

CVCL_0219

HCT15 cells

Colon

Homo sapiens (Human)

CVCL_0292

LS174T cells

Colon

Homo sapiens (Human)

CVCL_1384

NCI-H716 cells

Colon

Homo sapiens (Human)

CVCL_1581

SW948 cells

Colon

Homo sapiens (Human)

CVCL_0632

SW403 cells

Colon

Homo sapiens (Human)

CVCL_0545

SW48 cells

Colon

Homo sapiens (Human)

CVCL_1724

COLO205 cells

Colon

Homo sapiens (Human)

CVCL_F402

HuTu80 cells

Small intestine

Homo sapiens (Human)

CVCL_1301

LS123 cells

Colon

Homo sapiens (Human)

CVCL_1383

SK-CO-1 cells

Colon

Homo sapiens (Human)

CVCL_0626

SW837 cells

Colon

Homo sapiens (Human)

CVCL_1729

T84 cells

Colon

Homo sapiens (Human)

CVCL_0555

In Vivo Model

Nude mouse xenograft model

Mus musculus

Experiment for
Molecule Alteration

qPCR; Sequencing assay; Western blot analysis; Immunofluorescent staining assay

Experiment for
Drug Resistance

CCK8 assay

Mechanism Description

There is a double-negative feedback loop between MIR100HG and the transcription factor GATA6, whereby GATA6 represses MIR100HG, but this repression is relieved by miR125b targeting of GATA6.

Key Molecule: GTPase KRas (KRAS)

[12], [18], [19]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Missense mutation

p.G12V

Molecule Info

Wild Type Structure

Method: X-ray diffraction

Resolution: 1.98 Å

PDB: 7SCW

Mutant Type Structure

Method: X-ray diffraction

Resolution: 1.96 Å

PDB: 7SCX

Download The Information of Sequence

Download The Structure File

Click to Show/Hide the Structure

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

EGFR/RAS signaling pathway

Activation

hsa01521

In Vitro Model

LIM1215 cells

Colon

Homo sapiens (Human)

CVCL_2574

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Next-generation sequencing assay

Experiment for
Drug Resistance

Liquid biopsy assay

Mechanism Description

Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations (27780856). kRAS and EGFR ectodomain-acquired mutations in patients with metastatic colorectal cancer (mCRC) have been correlated with acquired resistance to anti-EGFR monoclonal antibodies (mAbs).

Key Molecule: GTPase KRas (KRAS)

[12]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Missense mutation

p.Q61H

Molecule Info

Wild Type Structure

Method: X-ray diffraction

Resolution: 1.31 Å

PDB: 6T5V

Mutant Type Structure

Method: X-ray diffraction

Resolution: 2.20 Å

PDB: 6MNX

Download The Information of Sequence

Download The Structure File

Click to Show/Hide the Structure

Experimental Note

Identified from the Human Clinical Data

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Next-generation sequencing assay

Experiment for
Drug Resistance

Liquid biopsy assay

Mechanism Description

Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Key Molecule: GTPase KRas (KRAS)

[12]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Missense mutation

p.G12D

Molecule Info

Wild Type Structure

Method: X-ray diffraction

Resolution: 1.40 Å

PDB: 6VJJ

Mutant Type Structure

Method: X-ray diffraction

Resolution: 2.10 Å

PDB: 8JHL

Download The Information of Sequence

Download The Structure File

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Experimental Note

Identified from the Human Clinical Data

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Next-generation sequencing assay

Experiment for
Drug Resistance

Liquid biopsy assay

Mechanism Description

Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF)

[12]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Missense mutation

p.V600E

Molecule Info

Wild Type Structure

Method: X-ray diffraction

Resolution: 2.55 Å

PDB: 4E26

Mutant Type Structure

Method: X-ray diffraction

Resolution: 3.20 Å

PDB: 4G9R

Download The Information of Sequence

Download The Structure File

Click to Show/Hide the Structure

Experimental Note

Identified from the Human Clinical Data

In Vitro Model

Colon cells

Colon

Homo sapiens (Human)

N.A.

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Next-generation sequencing assay

Experiment for
Drug Resistance

Liquid biopsy assay

Mechanism Description

Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Key Molecule: Hepatocyte growth factor receptor (MET)

[12]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Structural variation

Amplification

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Next-generation sequencing assay

Experiment for
Drug Resistance

Liquid biopsy assay

Mechanism Description

Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Key Molecule: GTPase KRas (KRAS)

[12]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Structural variation

Amplification

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Next-generation sequencing assay

Experiment for
Drug Resistance

Liquid biopsy assay

Mechanism Description

Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2)

[12]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Structural variation

Amplification

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Next-generation sequencing assay

Experiment for
Drug Resistance

Liquid biopsy assay

Mechanism Description

Mechanisms of resistance to EGFR blockade include the emergence of kRAS, NRAS and EGFR extracellular domain mutations as well as HER2/MET alterations.

Key Molecule: Hepatocyte growth factor receptor (MET)

[20]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Structural variation

Copy number gain

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Next-generation sequencing analysis; Gene copy number analysis

Mechanism Description

As amplification of the MET gene has recently been shown to drive resistance to anti-EGFR therapies, this copy number change is the best candidate to explain the poor treatment response.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2)

[21]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Structural variation

Amplification

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Experiment for
Molecule Alteration

Sanger sequencing assay; Next-generation sequencing assay

Mechanism Description

Mutations in kRAS, NRAS, and BRAF and amplification of ERBB2 and MET drive primary (de novo) resistance to anti-EGFR treatment.

Key Molecule: GTPase KRas (KRAS)

[22]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Mutation

Mutations in codons 12, 13 and 61

Molecule Info

Experimental Note

Identified from the Human Clinical Data

Cell Pathway Regulation

RAS/RAF/Mek/ERK signaling pathway

Activation

hsa04010

In Vitro Model

Colorectal cancer cells

Colon

Homo sapiens (Human)

N.A.

Experiment for
Molecule Alteration

High throughout experiment assay

Experiment for
Drug Resistance

Circulating tumor DNA analysis

Mechanism Description

The identification of kRAS mutations as a cause for intrinsic resistance of colorectal cancers also contributed to the identification of a mechanism for the acquired resistance. Establishment and analysis of cetuximabresistant colorectal cancer cell lines revealed that the resistant variants harbored kRAS point mutations or amplification, and the findings were confirmed in clinical specimens.

Key Molecule: Homeobox protein Hox-B8 (HOXB8)

[23]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

STAT3 signaling pathway

Activation

hsa04550

In Vitro Model

Caco2 cells

Colon

Homo sapiens (Human)

CVCL_0025

HCT-116 cells

Colon

Homo sapiens (Human)

CVCL_0291

Experiment for
Molecule Alteration

Western blot assay

Experiment for
Drug Resistance

MTT assay; Colony formation assay

Mechanism Description

By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.

Key Molecule: Signal transducer and activator of transcription 3 (STAT3)

[23]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Down-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

STAT3 signaling pathway

Activation

hsa04550

In Vitro Model

Caco2 cells

Colon

Homo sapiens (Human)

CVCL_0025

Experiment for
Molecule Alteration

Western blot assay

Experiment for
Drug Resistance

MTT assay; Colony formation assay

Mechanism Description

Key Molecule: Signal transducer and activator of transcription 3 (STAT3)

[23]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Cetuximab

Drug Info

Molecule Alteration

Expression

Up-regulation

Molecule Info

Experimental Note

Revealed Based on the Cell Line Data

Cell Pathway Regulation

STAT3 signaling pathway

Activation

hsa04550

In Vitro Model

HCT-116 cells

Colon

Homo sapiens (Human)

CVCL_0291

Experiment for
Molecule Alteration

Western blot assay

Experiment for
Drug Resistance

MTT assay; Colony formation assay

Mechanism Description

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-7				[24]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Cetuximab			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	microRNA-7 expression in colorectal cancer is associated with poor prognosis and regulates cetuximab sensitivity via EGFR regulation.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Epidermal growth factor receptor (EGFR)				[24]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Cetuximab			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	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	CCK8 assay
Mechanism Description	microRNA-7 expression in colorectal cancer is associated with poor prognosis and regulates cetuximab sensitivity via EGFR regulation.
Key Molecule: RAF proto-oncogene serine/threonine-protein kinase (RAF1)				[24]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Cetuximab			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	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	CCK8 assay
Mechanism Description	microRNA-7 expression in colorectal cancer is associated with poor prognosis and regulates cetuximab sensitivity via EGFR regulation.
Key Molecule: Homeobox protein Hox-B8 (HOXB8)				[23]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Cetuximab			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	STAT3 signaling pathway		Activation	hsa04550
In Vitro Model	SW48 cells	Colon	Homo sapiens (Human)	CVCL_1724
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay; Colony formation assay
Mechanism Description	By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.
Key Molecule: Signal transducer and activator of transcription 3 (STAT3)				[23]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Cetuximab			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	STAT3 signaling pathway		Activation	hsa04550
In Vitro Model	SW48 cells	Colon	Homo sapiens (Human)	CVCL_1724
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay; Colony formation assay
Mechanism Description	By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.

Chloroquine

Click to Show/Hide

Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: .				[25]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Chloroquine			Drug 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.

Cisplatin

Click to Show/Hide

Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-1271				[26]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Cisplatin			Drug 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	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	miR-1271 enhances the sensitivity of colorectal cancer cells to cisplatin via downregulating mTOP.
Key Molecule: hsa-mir-199a				[27]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Wnt/Beta-catenin signaling pathway		Regulation	N.A.
In Vitro Model	ALDHA1+ CCSCs cells	Colon	Homo sapiens (Human)	N.A.
In Vitro Model	ALDHA1 cells	Colon	Homo sapiens (Human)	N.A.
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Flow cytometry assay; MTT assay
Mechanism Description	Upregulation of miR199a/b contributes to cisplatin resistance via Wnt/beta-catenin-ABCG2 signaling pathway in ALDHA1+ colorectal cancer stem cells. Gsk3beta was the direct target of miR199a/b, miR199a/b regulates Wnt/beta-catenin pathway by targeting Gsk3beta in ALDHA1+ CCSCs.
Key Molecule: hsa-mir-199b				[27]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Wnt/Beta-catenin signaling pathway		Regulation	N.A.
In Vitro Model	ALDHA1+ CCSCs cells	Colon	Homo sapiens (Human)	N.A.
In Vitro Model	ALDHA1 cells	Colon	Homo sapiens (Human)	N.A.
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Flow cytometry assay; MTT assay
Mechanism Description	Upregulation of miR199a/b contributes to cisplatin resistance via Wnt/beta-catenin-ABCG2 signaling pathway in ALDHA1+ colorectal cancer stem cells. Gsk3beta was the direct target of miR199a/b, miR199a/b regulates Wnt/beta-catenin pathway by targeting Gsk3beta in ALDHA1+ CCSCs.
Key Molecule: Pvt1 oncogene (PVT1)				[28]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
	Intrinsic apoptotic signaling pathway		Inhibition	hsa04210
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
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; TUNEL assay; Flow cytometry assay
Mechanism Description	PVT1 involved in cisplatin resistance of CRC cells via upregulation of drug resistance-associated molecules, including multidrug resistance 1 (MDR1) and multidrug resistance protein 1 (MRP1), by blocking the intrinsic apoptotic pathway.
Key Molecule: hsa-mir-153				[29]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Cisplatin			Drug 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.
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: Multidrug resistance-associated protein 1 (MRP1)				[28]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
	Intrinsic apoptotic signaling pathway		Inhibition	hsa04210
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
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; TUNEL assay; Flow cytometry assay
Mechanism Description	PVT1 involved in cisplatin resistance of CRC cells via upregulation of drug resistance-associated molecules, including multidrug resistance 1 (MDR1) and multidrug resistance protein 1 (MRP1), by blocking the intrinsic apoptotic pathway.
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: microRNA-137 (miR-137)				[30]
Metabolic Type	Glutamine metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Cisplatin			Drug 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
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	SW-480 cells	Colon	Homo sapiens (Human)	CVCL_0546
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Using a microRNA (miRNA) microArray assay, miR-137, a tumor suppressor in colon cancer, was significantly induced by curcumin treatments in CRC cells. Bioinformatics analysis and a luciferase assay illustrated miR-137 directly targeted the 3' UTR of GLS mRNA. Rescue experiments demonstrated that miR-137-induced cisplatin sensitization was through targeting of GLS. Finally, curcumin treatment overcame cisplatin resistance through miR-137-mediated glutamine inhibition.
Key Molecule: YTH N6-methyladenosine RNA binding protein 1 (YTHDF1)				[31]
Metabolic Type	Glutamine metabolism
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Cisplatin			Drug 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
	HCT-116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	SW-480 cells	Colon	Homo sapiens (Human)	CVCL_0546
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Overexpression of YTHDF1 decreased the cisplatin sensitivity of colon cancer cells. From the established cisplatin-resistant CRC cell line (LoVo CDDP R), we detected that YTHDF1 was significantly upregulated in cisplatin-resistant CRC cells. Intriguingly, RNA sequencing (RNA-seq) results revealed that glutamine metabolism enzymes were clearly upregulated in LoVo CDDP R cells. Glutamine uptake, that is, glutaminase (GLS) activity, was upregulated in LoVo CDDP R cells. Furthermore, bioinformatics analysis indicated that the 3' UTR of GLS1 contained a putative binding motif of YTHDF1, and an interaction was further validated by a protein-RNA interaction assay (RNA immunoprecipitation [RIP]).
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase mTOR (mTOR)				[26]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Cisplatin			Drug 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	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
Experiment for Molecule Alteration	Western blot analysis; RT-qPCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	miR-1271 enhances the sensitivity of colorectal cancer cells to cisplatin via downregulating mTOP.
Key Molecule: Glycogen synthase kinase-3 beta (GSK3B)				[27]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Wnt/Beta-catenin signaling pathway		Regulation	N.A.
In Vitro Model	ALDHA1+ CCSCs cells	Colon	Homo sapiens (Human)	N.A.
In Vitro Model	ALDHA1 cells	Colon	Homo sapiens (Human)	N.A.
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis; Immunohistochemistry; Luciferase reporter assay
Experiment for Drug Resistance	Flow cytometry assay; MTT assay
Mechanism Description	Upregulation of miR199a/b contributes to cisplatin resistance via Wnt/beta-catenin-ABCG2 signaling pathway in ALDHA1+ colorectal cancer stem cells. Gsk3beta was the direct target of miR199a/b, miR199a/b regulates Wnt/beta-catenin pathway by targeting Gsk3beta in ALDHA1+ CCSCs.
Key Molecule: Forkhead box protein O3 (FOXO3)				[29]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Cisplatin			Drug 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 proliferation		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: Non-coding RNA activated by DNA damage (NORAD)				[32]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	miR-106a-5p/Cyclin D1 signalling pathway		Regulation	N.A.
In Vitro Model	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Clonogenic assay
Mechanism Description	In the established cisplatin resistant cell line, NORAD was upregulated and miR-106a-5p was downregulated. Furthermore, we disclosed miR-106a-5p directly targeted 3'UTR of CCND1, which is an important cell cycle regulator and is frequently overexpressed in human cancers. Rescue experiments showed restoration of CCND1 in miR-106a-5p-overexpressing CRC cells successfully recovered cisplatin resistance. Finally, restoration of miR-106a-5p in NORAD-overexpressing CRC cells re-sensitized cisplatin resistance by targeting CCND1. Summarily, this study uncovered a NORAD-promoted cisplatin resistance through modulating the miR-106a-5p-CCND1 axis.
Key Molecule: hsa-miR-106a-5p				[32]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	miR-106a-5p/Cyclin D1 signalling pathway		Regulation	N.A.
In Vitro Model	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Clonogenic assay
Mechanism Description	In the established cisplatin resistant cell line, NORAD was upregulated and miR-106a-5p was downregulated. Furthermore, we disclosed miR-106a-5p directly targeted 3'UTR of CCND1, which is an important cell cycle regulator and is frequently overexpressed in human cancers. Rescue experiments showed restoration of CCND1 in miR-106a-5p-overexpressing CRC cells successfully recovered cisplatin resistance. Finally, restoration of miR-106a-5p in NORAD-overexpressing CRC cells re-sensitized cisplatin resistance by targeting CCND1. Summarily, this study uncovered a NORAD-promoted cisplatin resistance through modulating the miR-106a-5p-CCND1 axis.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-148a				[33]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Beta-catenin signaling pathway		Inhibition	hsa04520
	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell viability		Inhibition	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	MTT assay; Flow cytometry assay
Mechanism Description	Overexpression of miR-148a suppressed expression of stem cell markers, inhibited sphere formation, invasion and migration, induced apoptosis, and reduced chemo-resistance in cisplatin-resistant SW480 cells while suppressing WNT10b expression and beta-catenin signaling activities.
Key Molecule: hsa-mir-20a				[34]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Cisplatin			Drug 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
	ROS/ASk1/JNk signaling pathway		Activation	hsa04071
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
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	Knockdown of miR-20a enhanced sensitivity of colorectal cancer cells to cisplatin through the ROS/ASk1/JNk pathway.
Key Molecule: hsa-mir-497				[35]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Cisplatin			Drug 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
	MEK/ERK signaling pathway		Inhibition	hsa04011
	PI3K/AKT signaling pathway		Inhibition	hsa04151
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
	COLO 205 cells	Colon	Homo sapiens (Human)	CVCL_0218
	HCT28 cells	Colon	Homo sapiens (Human)	N.A.
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	IGF1-R has an important role in mediating activation of the PI3k/Akt pathway, miR-497 inhibits PI3k/Akt signalling. Down-regulation of miR-497 is an important mechanism of upregulation of IGF1-R in CRC cells that contributes to malignancy of CRC.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Protein Wnt-10b (WNT10B)				[33]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Beta-catenin signaling pathway		Inhibition	hsa04520
	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell viability		Inhibition	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	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Overexpression of miR-148a suppressed expression of stem cell markers, inhibited sphere formation, invasion and migration, induced apoptosis, and reduced chemo-resistance in cisplatin-resistant SW480 cells while suppressing WNT10b expression and beta-catenin signaling activities.
Key Molecule: Mitogen-activated protein kinase kinase kinase 5 (MAP3K5)				[34]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Phosphorylation		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell viability		Inhibition	hsa05200
	ROS/ASk1/JNk signaling pathway		Activation	hsa04071
In Vitro Model	HT29 Cells	Colon	Homo sapiens (Human)	CVCL_A8EZ
	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
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
Mechanism Description	Knockdown of miR-20a enhanced sensitivity of colorectal cancer cells to cisplatin through the ROS/ASk1/JNk pathway.
Key Molecule: Insulin-like growth factor 1 receptor (IGF1R)				[35]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Cisplatin			Drug Info
Molecule Alteration	Expression		Down-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
	MEK/ERK signaling pathway		Inhibition	hsa04011
	PI3K/AKT signaling pathway		Inhibition	hsa04151
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
	COLO 205 cells	Colon	Homo sapiens (Human)	CVCL_0218
	HCT28 cells	Colon	Homo sapiens (Human)	N.A.
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTS assay
Mechanism Description	IGF1-R has an important role in mediating activation of the PI3k/Akt pathway, miR-497 inhibits PI3k/Akt signalling. Down-regulation of miR-497 is an important mechanism of upregulation of IGF1-R in CRC cells that contributes to malignancy of CRC.

Colchicine

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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: ATP-binding cassette sub-family B5 (ABCB5)				[36]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]
Sensitive Drug	Colchicine			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	CaCo2 cells	Colon	Homo sapiens (Human)	CVCL_0025
	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
	NIH-G185 cells	Ovary	Homo sapiens (Human)	CVCL_L991
	NIH 3T3 cells	Colon	Homo sapiens (Human)	CVCL_0594
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	G185 cells were 27-135 fold more resistant to the cytotoxic drugs doxorubicin, vinblastine, colchicine and paclitaxel than the parental NIH 3T3 cells. Co-administration of TPGS enhanced the cytotoxicity of doxorubicin, vinblastine, paclitaxel, and colchicine in the G185 cells to levels comparable to the parental.

Dabrafenib/Trametinib

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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Key Molecule: Serine/threonine-protein kinase B-raf (BRAF)

[37]

Sensitive Disease

Colorectal cancer [ICD-11: 2B91.1]

Sensitive Drug

Dabrafenib/Trametinib

Drug Info

Molecule Alteration

Missense mutation

p.V600E (c.1799T>A)

Molecule Info

Wild Type Structure

Method: X-ray diffraction

Resolution: 2.55 Å

PDB: 4E26

Mutant Type Structure

Method: X-ray diffraction

Resolution: 3.20 Å

PDB: 4G9R

Download The Information of Sequence

Download The Structure File

Click to Show/Hide the Structure

Experimental Note

Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF)

[38]

Sensitive Disease

Colorectal cancer [ICD-11: 2B91.1]

Sensitive Drug

Dabrafenib/Trametinib

Drug Info

Molecule Alteration

Missense mutation

p.V600X (c.1798_1800)

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vitro Model

Colorectum

N.A.

In Vivo Model

Patient-Derived xenograft mouse model

Mus musculus

Experiment for
Molecule Alteration

Reverse-phase protein array (RPPA) analysis; Targeted next-generation sequencing (NGS) assay

Experiment for
Drug Resistance

Immunohistochemistry assay

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF)

[38]

Sensitive Disease

Colorectal cancer [ICD-11: 2B91.1]

Sensitive Drug

Dabrafenib/Trametinib

Drug Info

Molecule Alteration

Missense mutation

p.V600X (c.1798_1799)

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vitro Model

Colorectum

N.A.

In Vivo Model

Patient-Derived xenograft mouse model

Mus musculus

Experiment for
Molecule Alteration

Reverse-phase protein array (RPPA) analysis; Targeted next-generation sequencing (NGS) assay

Experiment for
Drug Resistance

Immunohistochemistry assay

Docetaxel

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Drug Resistance 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)				[39]
Resistant Disease	Colorectal carcinoma [ICD-11: 2B91.3]
Resistant Drug	Docetaxel			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
In Vivo Model	Athymic nu/nu female mice xenograft model			Mus musculus
Experiment for Drug Resistance	MTS assay
Mechanism Description	In a cell line expressing a high level of P-glycoprotein, the IC50 of TTI-237 increased 25-fold whereas those of paclitaxel and vincristine increased 806-fold and 925-fold.

Doxorubicin

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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: Glycogen synthase kinase-3 beta (GSK3B)				[40]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Wnt/Beta-catenin signaling pathway		Regulation	N.A.
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	SW480/ADM cells	Colon	Homo sapiens (Human)	CVCL_0546
Experiment for Molecule Alteration	Dual luciferase gene reporter assay
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay; EdU staining
Mechanism Description	miR224 up-regulation is associated with ADM resistance of CRC cells. Suppression of miR224 expression up-regulated GSk-3beta expression, inhibited Wnt/beta-catenin signal pathway activity and Survivin expression, as well as reduced ADM resistance of CRC SW480 cells.
Key Molecule: hsa-mir-224				[40]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Wnt/Beta-catenin signaling pathway		Regulation	N.A.
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	SW480/ADM cells	Colon	Homo sapiens (Human)	CVCL_0546
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay; EdU staining
Mechanism Description	miR224 up-regulation is associated with ADM resistance of CRC cells. Suppression of miR224 expression up-regulated GSk-3beta expression, inhibited Wnt/beta-catenin signal pathway activity and Survivin expression, as well as reduced ADM resistance of CRC SW480 cells.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: SLC25A25 antisense RNA 1 (SLC25A25-AS1)				[41]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Doxorubicin			Drug 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		Activation	hsa05200
	ERK/p38 signaling pathway		Inhibition	hsa04210
In Vitro Model	HCT116 cells	Colon	Homo sapiens (Human)	CVCL_0291
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	SLC25A25-AS1 overexpression significantly inhibited proliferation and colony formation in colorectal cancer cell lines, and downregulation of SLC25A25-AS1 obviously (+) chemoresistance and promoted EMT process in vitro associated with Erk and p38 signaling pathway activation. Therefore, SLC25A25-AS1 was determined to play a tumor suppressive role in CRC.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Drug Inactivation by Structure Modification (DISM)			Click to Show/Hide
Key Molecule: Cytochrome P450 family 3 subfamily A member1 (CYP3A4)				[42]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	CaCo2 cells	Colon	Homo sapiens (Human)	CVCL_0025
Experiment for Molecule Alteration	CYP450-Glo CYP 3A4 assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	In this study, resveratrol was a significant inhibitor of CYP3A4 enzyme activity with IC50 value 9.32 ( M). Moreover, the CYP3A4 mRNA levels were reduced after treatment with resveratrol 0.03-fold of the control levels with high significance (p < 0.001).
Key Molecule: Glutathione S-transferase (GST)				[42]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	CaCo2 cells	Colon	Homo sapiens (Human)	CVCL_0025
Experiment for Molecule Alteration	Glutathione-S-transferase assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	The Glutathione-S-transferases (GSTs) are a multigene family of dimeric proteins which play a central role in the detoxification of electrophilic xenobiotics and catalyze their conjugation with GSH to electrophilic metabolites, thus rendering them more water soluble. GSTs protect cells from cytotoxic and carcinogenic chemicals. GST activity was decreased by resveratrol in a dose dependent manner. IC50 value was 30.73 M. This results were confirmed by RT-PCR data, where the tested samples changed the GST mRNA level by 0.79-fold (p < 0.01) of control level.
Irregularity in Drug Uptake and Drug Efflux (IDUE)			Click to Show/Hide
Key Molecule: ATP-binding cassette sub-family B5 (ABCB5)				[43]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]
Sensitive Drug	Doxorubicin			Drug 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
In Vitro Model	HCT8 cells	Colon	Homo sapiens (Human)	CVCL_2478
	CT26 cells	Colon	Mus musculus (Mouse)	CVCL_7254
	Salmonella enterica serovar Typhimurium SL1344			216597
	Salmonella enterica serovar Typhimurium SL1344 detaSipA			216597
	Salmonella enterica serovar Typhimurium SL1344 detaSipB			216597
	Salmonella enterica serovar Typhimurium SL1344 detaSipC			216597
	Salmonella enterica serovar Typhimurium SL1344 detaSopB			216597
In Vivo Model	BALB/c mice xenograft model			Mus musculus
Experiment for Drug Resistance	MTS assay
Mechanism Description	Mimicking the ability of Salmonella to reverse multidrug resistance, we constructed a gold nanoparticle system packaged with a SipA corona, and found this bacterial mimic not only accumulates in tumours but also reduces P-gp at a SipA dose significantly lower than free SipA. Moreover, the Salmonella nanoparticle mimic suppresses tumour growth with a concomitant reduction in P-gp when used with an existing chemotherapeutic drug (that is, doxorubicin).
Key Molecule: ATP-binding cassette sub-family B5 (ABCB5)				[36]
Sensitive Disease	Colorectal carcinoma [ICD-11: 2B91.3]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	CaCo2 cells	Colon	Homo sapiens (Human)	CVCL_0025
	HCT-8 cells	Colon	Homo sapiens (Human)	CVCL_2478
	NIH-G185 cells	Ovary	Homo sapiens (Human)	CVCL_L991
	NIH 3T3 cells	Colon	Homo sapiens (Human)	CVCL_0594
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	G185 cells were 27-135 fold more resistant to the cytotoxic drugs doxorubicin, vinblastine, colchicine and paclitaxel than the parental NIH 3T3 cells. Co-administration of TPGS enhanced the cytotoxicity of doxorubicin, vinblastine, paclitaxel, and colchicine in the G185 cells to levels comparable to the parental.
Key Molecule: ATP-binding cassette sub-family B5 (ABCB5)				[42]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	CaCo2 cells	Colon	Homo sapiens (Human)	CVCL_0025
Experiment for Molecule Alteration	Efflux of rhodamine123 assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	Resveratrol can restore the sensitivity of Caco-2 and CEM/ADR5000 cell lines to doxorubicin, through enhancing significantly doxorubicin cytotoxicity. ABC-transporter inhibitors, classified according to their action on ABC-transporters proteins into: 1. Function inhibitors, 2. Expression inhibitors, and 3. Functional and expression inhibitors, which have an ideal characters of ABC-transporters inhibitors. Our results indicate that resveratrol falls into the class 3 inhibitors.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: F-box/WD repeat-containing protein 7 (FBXW7)				[44]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
	miR223/FBXW7 signaling pathway		Regulation	N.A.
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Overexpression of miR-223 decreased FBXW7 expression and the sensitivity of CRC cells to doxorubicin, while suppression of miR-223 had the opposite effect.
Key Molecule: hsa-mir-223				[44]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
	miR223/FBXW7 signaling pathway		Regulation	N.A.
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	SW620 cells	Colon	Homo sapiens (Human)	CVCL_0547
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Overexpression of miR-223 decreased FBXW7 expression and the sensitivity of CRC cells to doxorubicin, while suppression of miR-223 had the opposite effect.

Entrectinib

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Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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Key Molecule: Tropomyosin-related kinase A (TrkA)

[45]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Entrectinib

Drug Info

Molecule Alteration

Missense mutation

p.G595R (c.1783G>A)

Molecule Info

Wild Type Structure

Method: X-ray diffraction

Resolution: 2.10 Å

PDB: 5H3Q

Mutant Type Structure

Method: X-ray diffraction

Resolution: 2.09 Å

PDB: 8J5X

Download The Information of Sequence

Download The Structure File

Click to Show/Hide the Structure

Experimental Note

Identified from the Human Clinical Data

In Vitro Model

KM-12 cells

Colon

Homo sapiens (Human)

CVCL_1331

In Vivo Model

NOD-SCID mouse xenograft model

Mus musculus

Experiment for
Molecule Alteration

ddPCR; Kinase domain alignment assay

Key Molecule: Tropomyosin-related kinase A (TrkA)

[45]

Resistant Disease

Colorectal cancer [ICD-11: 2B91.1]

Resistant Drug

Entrectinib

Drug Info

Molecule Alteration

Missense mutation

p.G667C (c.1999G>T)

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vitro Model

KM-12 cells

Colon

Homo sapiens (Human)

CVCL_1331

In Vivo Model

NOD-SCID mouse xenograft model

Mus musculus

Experiment for
Molecule Alteration

ddPCR; Kinase domain alignment assay

Fentanyl

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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: BRAF-activated non-protein coding RNA (BANCR)				[46]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fentanyl			Drug 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 invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Transwell assay
Mechanism Description	Fentanyl inhibits the invasion and migration of colorectal cancer cells via inhibiting the negative regulation of Ets-1 on BANCR.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Protein C-ets-1 (ETS1)				[46]
Resistant Disease	Colorectal cancer [ICD-11: 2B91.1]
Resistant Drug	Fentanyl			Drug 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 invasion		Activation	hsa05200
	Cell migration		Activation	hsa04670
	Cell proliferation		Activation	hsa05200
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	LOVO cells	Colon	Homo sapiens (Human)	CVCL_0399
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	Transwell assay
Mechanism Description	Fentanyl inhibits the invasion and migration of colorectal cancer cells via inhibiting the negative regulation of Ets-1 on BANCR.

Clinical Trial Drug(s)

1 drug(s) in total

Click to Show/Hide the Full List of Drugs

TRAIL

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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: BH3-interacting domain death agonist (BID)				[5]
Sensitive Disease	Colorectal cancer [ICD-11: 2B91.1]
Sensitive Drug	TRAIL			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Colorectal cancer [ICD-11: 2B91]
The Specified Disease	Colorectal cancer
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.45E-74 Fold-change: 1.65E+00 Z-score: 2.47E+01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	TBID/Mitochondria signaling pathway		Activation	hsa04217
In Vitro Model	SW480 cells	Colon	Homo sapiens (Human)	CVCL_0546
	NCI-H508 cells	Colon	Homo sapiens (Human)	CVCL_1564
	HT-29 cells	Colon	Homo sapiens (Human)	CVCL_0320
	SW948 cells	Colon	Homo sapiens (Human)	CVCL_0632
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; FITC-Annexin V and propidium iodide (PI) assay
Mechanism Description	The knockdown of miR20a inhibited the translocation of tBID to the mitochondria, which induced the mitochondrial pathway of apoptosis, the knockdown of miR20a also reversed the resistance of TRAIL in established TRAIL-resistant SW480 cells by tBID-mitochondria pathway.

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