Drug Information

Drug (ID: DG01265) and It's Reported Resistant Information

• Name: Palbociclib
• Synonyms: Palbociclib; 571190-30-2; PD-0332991; Ibrance; PD0332991; PD 0332991; UNII-G9ZF61LE7G; Palbociclib free base; 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one; PD-332991; 571190-30-2 (free base); MFCD11840850; 6-ACETYL-8-CYCLOPENTYL-5-METHYL-2-[(5-PIPERAZIN-1-YLPYRIDIN-2-YL)AMINO]PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE; 6-Acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl)pyridin-2-yl]amino]-8H-pyrido[2,3-d]pyrimidin-7-one; G9ZF61LE7G; Palbociclib(PD0332991); PD 332991; 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-ylpyridin-2-ylamino)-8H-pyrido(2,3-d)pyrimidin-7-one; CHEBI:85993; 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7-one; 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one; LQQ; C24H29N7O2; 2euf; 571190-30-2 pound not827022-32-2; Palbociclib [USAN:INN]; [d8]-Palbociclib; Ibrance (TN); Palbociclib- Bio-X; Kinome_3823; Kinome_3824; 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8h-pyrido[2,3-d]pyrimidin-7-one hydrochloride; Palbociclib (JAN/USAN); SCHEMBL462630; BDBM6309; CHEMBL189963; GTPL7380; PD 0332991 (Palbociclib); DTXSID40972590; EX-A408; QCR-200; 2euf; PD 0332991; OTAVA-BB 1115529; BCPP000125; HMS3265M09; HMS3265M10; HMS3265N09; HMS3265N10; HMS3744G13; AMY14886; AOB87334; BCP09274; BCP18381; ZINC3938686; NSC758247; NSC772256; NSC800815; s4482; AKOS022205241; BCP9001058; CA10003; DB09073; NSC-758247; NSC-772256; NSC-800815; SB40426; Pyrido-[2,3-d]-pyrimidin-7-one 43; NCGC00263129-01; NCGC00263129-08; NCGC00263129-21; NCGC00263129-22; AC-25485; AS-17016; BP166224; HY-50767; SY026143; FT-0697059; X7379; A14427; D10372; 190P302; PD 0332991,PD0332991; PD-0332991, PD0332991; BRD-K51313569-001-01-1; P-0332991; Q15269707; 6-Acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one; 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrido[6,5-d]pyrimidin-7-one; 6-Acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one; 6-Acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl)-pyridin-2-yl]amino]-8H-pyrido[2,3-d]pyrimidin-7-one; 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H,8H-pyrido[2,3-d]pyrimidin-7-one; 8-cyclopentyl-6-acetyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H,8H-pyrido[2,3-d]pyrimidin-7-one; Pyrido(2,3-d)pyrimidin-7(8H)-one, 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(1-piperazinyl)-2-pyridinyl)amino)-
• Indication:
  In total 3 Indication(s)
  Breast cancer [ICD-11: 2C60]; Approved; [1]
  Schizophrenia [ICD-11: 6A20]; Approved; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (3 diseases)
  Breast cancer [ICD-11: 2C60]; [2]
  Lung cancer [ICD-11: 2C25]; [4]
  Oral squamous cell carcinoma [ICD-11: 2B6E]; [5]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Breast cancer [ICD-11: 2C60]; [3]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Breast cancer [ICD-11: 2C60]; [1]
• Target: Cyclin-dependent kinase 4 (CDK4); CDK4_HUMAN; [2]
• Target: Cyclin-dependent kinase 6 (CDK6); CDK6_HUMAN; [2]
• Formula: C24H29N7O2
• IsoSMILES: CC1=C(C(=O)N(C2=NC(=NC=C12)NC3=NC=C(C=C3)N4CCNCC4)C5CCCC5)C(=O)C
• InChI: 1S/C24H29N7O2/c1-15-19-14-27-24(28-20-8-7-18(13-26-20)30-11-9-25-10-12-30)29-22(19)31(17-5-3-4-6-17)23(33)21(15)16(2)32/h7-8,13-14,17,25H,3-6,9-12H2,1-2H3,(H,26,27,28,29)
• InChIKey: AHJRHEGDXFFMBM-UHFFFAOYSA-N
• PubChem CID: 5330286
• ChEBI ID: CHEBI:85993
• TTD Drug ID: D00UZR
• VARIDT ID: DR01288
• INTEDE ID: DR1229
• DrugBank ID: DB09073

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cyclin dependent kinase 7 (CDK7) [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Breast cancer [ICD-11: 2C60]
• The Specified Disease: Breast cancer
• The Studied Tissue: Breast tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.85E-35; Fold-change: 9.86E-02; Z-score: 1.38E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: CDK7 is a cell cycle regulator. In addition, it also acts as a transcription factor, after complexation with cyclin H and MAT1. Increased expression of CDK7 is reported to confer resistance to CDK4/6 inhibitors. It acts as a CDK-activating kinase (CAK) and is involved in the G2/M phase by maintaining CDK1 and CDK2 activity.

Key Molecule: Histone deacetylase 1 (HDAC1) [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Breast cancer [ICD-11: 2C60]
• The Specified Disease: Breast cancer
• The Studied Tissue: Breast tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.67E-33; Fold-change: 6.64E-02; Z-score: 1.32E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Although the involvement of HDAC in resistance to CDK4/6 inhibitors is currently unknown, inhibition of HDAC may increase the efficacy of CDK4/6 inhibitors in CDK4/6 inhibitor-resistant cells by activating p21, resulting in cell cycle arrest at the G1 and G2/M phases, as demonstrated in CDK4/6 inhibitor-sensitive cells.

Key Molecule: E3 ubiquitin-protein ligase Mdm2 (MDM2) [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Breast cancer [ICD-11: 2C60]
• The Specified Disease: Breast cancer
• The Studied Tissue: Breast tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.54E-23; Fold-change: 5.01E-02; Z-score: 1.02E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Approximately 20%-30% of breast cancer patients show overexpression of MDM2, and this overexpression contributes particularly to the progression of HR-positive breast cancer. It is reported that CDK4/6 inhibitor-resistant cells have disrupted senescence pathways and insensitivity to the induction of senescence. Therefore, interruption of the senescence pathway by MDM2 in a p53-dependent manner may cause resistance to CDK4/6 inhibitors.

Key Molecule: Wee1-like protein kinase (WEE1) [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Breast cancer [ICD-11: 2C60]
• The Specified Disease: Breast cancer
• The Studied Tissue: Breast tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.38E-02; Fold-change: 2.39E-02; Z-score: 2.47E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: WEE1 plays an important role in the G2/M checkpoint. It inhibits the entry of DNA-damaged cells into mitosis in coordination with CDK1. Though the involvement of WEE1 in inducing resistance to CDK4/6 inhibitors is unknown, inhibition of WEE1 has been shown to increase sensitivity to CDK4/6 inhibitors in resistant cells. As WEE1 is associated with a resistant phenotype in preclinical models, targeting the G2/M phase via the inhibition of WEE1 in combination with CDK4/6 inhibition could be a therapeutic option in overcoming resistance.

Key Molecule: Cyclin-dependent kinase inhibitor 2A (CDKN2A) [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Breast cancer [ICD-11: 2C60]
• The Specified Disease: Breast cancer
• The Studied Tissue: Breast tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.16E-27; Fold-change: 1.60E-01; Z-score: 1.12E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Overexpression of p16 occurs during oncogenic stress, with or without the loss of RB. Loss of RB with concurrent p16 overexpression resulted in failure to respond to CDK4/6 inhibitors because of the absence of RB function. Alternatively, p16 overexpression in the presence of functional RB, also confers resistance to CDK4/6 inhibitors as a result of diminished CDK4, indicating depletion of a target of CDK4/6 inhibitors. Although the loss of RB and p16 overexpression seems to occur consequently together, further studies revealing the mechanistic association of RB loss and p16 overexpression might be beneficial in designing the strategies to overcome acquired resistance to CDK4/6 inhibitors.

Key Molecule: Estrogen receptor alpha (ESR1) [2]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Missense mutation; p.Y537S
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.60 Å; PDB: 2IOG
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.50 Å; PDB: 5DXE

RMSD: 1.7; TM score: 0.91757; Amino acid change: Y537S

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Breast cancer tissue; N.A.
• Experiment for Molecule Alteration: Digital PCR assay
• Mechanism Description: We show that clonal evolution occurs frequently during treatment, reflecting substantial sub-clonal complexity in breast cancer that has progressed after prior endocrine therapy. RB1 mutations emerged only in the palbociclib plus fulvestrant arm and in a minority of patients (6/127, 4.7%, p=0.041). New driver mutations emerged in PIK3CA (p=0.00069) and ESR1 after treatment in both arms, in particular ESR1 Y537S (p=0.0037). Evolution of driver gene mutations was uncommon in patients progressing early on palbociclib plus fulvestrant but common in patients progressing later on treatment. These findings inform future treatment strategies to address resistance to palbociclib plus fulvestrant.

Key Molecule: Mothers against decapentaplegic homolog 3 (SMAD3) [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Smad3 is a component of the TGF-beta signaling pathway, having antiproliferative effects that contribute to G1 cell cycle arrest. From this perspective, it was demonstrated that the suppression of Smad3 was involved in mechanisms responsible for resistance to certain anticancer drugs, such as trastzumab. Furthermore, some evidences suggested that Smad3 may be correlated with resistance to CDK4/6 inhibitors. Mechanistically, Smad3 was reported to be suppressed through phosphorylation by the cyclin E-CDK2 or cyclin D1-CDK4/6 complexes.

Key Molecule: Fibroblast growth factor receptor (FGFR) [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FGFR signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa05235
• Cell Pathway Regulation: RAS/MEK/ERK signaling pathway; Activation; hsa04010
• Mechanism Description: The FGFR pathway is frequently activated in several types of cancer, including breast cancer. Of the five FGFRs, FGFR 1-4 have been reported to play an important role in cancer progression. Furthermore, FGFR1 and FGFR2 also appear to be associated with resistance to CDK4/6 inhibitors, as well as with endocrine resistance. Mechanistic investigation showed that FGFR1 amplification activated the PI3K/AKT and RAS/MEK/ERK signaling pathways in endocrine-resistant breast cancer cells.

Key Molecule: Transcription factor E2F2 (E2F2) [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: The overexpression of E2F causes the cell to circumvent CDK4/6 inhibition and rely upon signaling pathways other than the cyclin D-CDK4/6 axis for cell cycle progression. Further studies are required to explore the detailed mechanism of this escape pathway. Moreover, inhibition of proteins downstream of E2F, in concert with CDK4/6 inhibition, may increase the efficacy of CDK4/6 inhibitors, overcoming resistance.

Key Molecule: Retinoblastoma-like protein 1 (RBL1) [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: The tumor suppressor RB is the aforementioned key checkpoint in the cell cycle. As the primary target of CDK4/6 inhibitors, RB was considered to be one of the most important biomarkers of sensitivity to therapy. In this scenario, loss of RB is the evident cause of resistance to CDK4/6 inhibitors, and various preclinical studies have supported this hypothesis. In addition, some preclinical and clinical studies have also reported that mutations in RB are responsible for the resistance. A study using glioblastoma xenograft cells, a missense mutation in exon 2 of RB(A193T) resulted in resistance to CDK4/6 inhibitors.

Key Molecule: Retinoblastoma-like protein 1 (RBL1) [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Missense mutation; p.A193T
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: The tumor suppressor RB is the aforementioned key checkpoint in the cell cycle. As the primary target of CDK4/6 inhibitors, RB was considered to be one of the most important biomarkers of sensitivity to therapy. In this scenario, loss of RB is the evident cause of resistance to CDK4/6 inhibitors, and various preclinical studies have supported this hypothesis. In addition, some preclinical and clinical studies have also reported that mutations in RB are responsible for the resistance. A study using glioblastoma xenograft cells, a missense mutation in exon 2 of RB(A193T) resulted in resistance to CDK4/6 inhibitors.

Key Molecule: Fizzy and cell division cycle 20 related 1 (FZR1) [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: The ubiquitin (Ub) ligase APC/C, which is activated via the co-activator FZR1, interacts with RB during the G1 phase of cell cycle. More notably, APC/CFZR1 complex degrades S-phase kinase associated protein 2 (SKP2), which inhibits p27, natural CDK inhibitors, resulting in decreased CDK2, CDK4 and CDK6. Accordingly, the loss of FZR1 results in uncontrolled cell cycle progression from G1 to S phase.

Key Molecule: Retinoblastoma-associated protein (RB1) [11]

• Resistant Disease: ER positive breast cancer [ICD-11: 2C60.6]
• Molecule Alteration: FS-insertion; p.M695fs*26 (c.2083_2084insC)
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• Mechanism Description: The combination of CDK4/6 and PI3K inhibition induces a different mode of arrest compared with palbociclib alone, characterized by not only sustained growth arrest, but also increased apoptosis in vitro, as well as tumor regression in vivo.

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Cyclin-dependent kinase 4 (CDK4) [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Breast cancer [ICD-11: 2C60]
• The Specified Disease: Breast cancer
• The Studied Tissue: Breast tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.29E-37; Fold-change: 5.96E-02; Z-score: 1.38E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Various mechanisms, such as gene amplification, mutations and epigenetic alterations, serve to activate the cyclin D-CDK4/6-RB pathway. Overexpression of CDK4, which has been described in several cancers, may limit the efficacy of CDK4/6 inhibitors.

Key Molecule: Cyclin-dependent kinase 6 (CDK6) [1]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: In some studies, CDK6 overexpression was reported to promote resistance to CDK4/6 inhibitors in preclinical models. Possible mechanisms how CDK6 amplification confers resistance to CDK4/6 inhibitor might be due to kinase-independent function of CDK6, which involves VEGF-A or p16.

Key Molecule: Epithelial discoidin domain-containing receptor 1 (DDR1) [3]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Molecule Alteration: Expressiom; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: TFAP2C-DDR1 signaling pathway; Regulation; N.A.
• In Vitro Model: T-47D cells; N.A.; Homo sapiens (Human); CVCL_0553
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: The comprehensive analyses revealed DDR1 as a potential factor implicated in mediating resistance to CDK4/6i. Specifically, DDR1 inhibition in combination with palbociclib exhibited remarkable synergistic effects, reducing cell survival signaling and promoting apoptosis in resistant cells. In-vivo xenograft model further validated the synergistic effects, showing a significant reduction in the resistant tumor growth. Exploration into DDR1 activation uncovered TFAP2C as a key transcription factor regulating DDR1 expression in palbociclib resistant cells and inhibition of TFAP2C re-sensitized resistant cells to palbociclib. Gene set enrichment analysis (GSEA) in the NeoPalAna trial demonstrated a significant enrichment of the TFAP2C-DDR1 gene set from patitens after palbociclib treatment, suggesting the possible activation of the TFAP2C-DDR1 axis following palbociclib exposure.

Key Molecule: Epithelial discoidin domain-containing receptor 1 (DDR1) [3]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Molecule Alteration: Expressiom; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: TFAP2C-DDR2 signaling pathway; Regulation; N.A.
• In Vitro Model: MCF7 cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: The comprehensive analyses revealed DDR1 as a potential factor implicated in mediating resistance to CDK4/6i. Specifically, DDR1 inhibition in combination with palbociclib exhibited remarkable synergistic effects, reducing cell survival signaling and promoting apoptosis in resistant cells. In-vivo xenograft model further validated the synergistic effects, showing a significant reduction in the resistant tumor growth. Exploration into DDR1 activation uncovered TFAP2C as a key transcription factor regulating DDR1 expression in palbociclib resistant cells and inhibition of TFAP2C re-sensitized resistant cells to palbociclib. Gene set enrichment analysis (GSEA) in the NeoPalAna trial demonstrated a significant enrichment of the TFAP2C-DDR1 gene set from patitens after palbociclib treatment, suggesting the possible activation of the TFAP2C-DDR1 axis following palbociclib exposure.

Key Molecule: Epithelial discoidin domain-containing receptor 1 (DDR1) [3]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Molecule Alteration: Expressiom; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: TFAP2C-DDR0 signaling pathway; Regulation; N.A.
• In Vivo Model: Breast cancer xenograft model; Mus musculus
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: The comprehensive analyses revealed DDR1 as a potential factor implicated in mediating resistance to CDK4/6i. Specifically, DDR1 inhibition in combination with palbociclib exhibited remarkable synergistic effects, reducing cell survival signaling and promoting apoptosis in resistant cells. In-vivo xenograft model further validated the synergistic effects, showing a significant reduction in the resistant tumor growth. Exploration into DDR1 activation uncovered TFAP2C as a key transcription factor regulating DDR1 expression in palbociclib resistant cells and inhibition of TFAP2C re-sensitized resistant cells to palbociclib. Gene set enrichment analysis (GSEA) in the NeoPalAna trial demonstrated a significant enrichment of the TFAP2C-DDR1 gene set from patitens after palbociclib treatment, suggesting the possible activation of the TFAP2C-DDR1 axis following palbociclib exposure.

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Diacylglycerol kinase gamma (DGKGgamma) [10]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Triple-negative breast cancer [ICD-11: 2C60.9]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-231cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MFM-223 cells; Pleural effusion; Homo sapiens (Human); CVCL_1408
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: This study aims to identify differentially expressed genes (DEG) associated with acquired resistance to palbociclib in ER- breast cancer cells.

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Histone H3 [5]

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

Gastric cancer [ICD-11: 2B72]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Cyclin-dependent kinase inhibitor 2A (CDKN2A) [6]

• Sensitive Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Molecule Alteration: Nonsense; p.R80* (c.238C>T)
• Experimental Note: Identified from the Human Clinical Data

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Cyclin-dependent kinase 4 (CDK4) [4]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Copy number gain; .
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [4]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Copy number gain; .
• Experimental Note: Identified from the Human Clinical Data

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase KRas (KRAS) [7]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.G12V (c.35G>T)
• 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

RMSD: 0.47; TM score: 0.99104; Amino acid change: G12V

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Human NSCLC cells; Lung; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.G12V (c.35G>T) in gene KRAS cause the sensitivity of Palbociclib by unusual activation of pro-survival pathway

Key Molecule: Transcription activator BRG1 (BRG1) [8]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Copy number loss; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NCI-H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: NCI-H1299 cells; Lymph node; Homo sapiens (Human); CVCL_0060
• In Vivo Model: Female YFP/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-blue assay
• Mechanism Description: SMARCA4/2 loss reduces cyclin D1 expression by a combination of restricting CCND1 chromatin accessibility and suppressing c-Jun, a transcription activator of CCND1. Reduced cyclin D1 in SMARCA4-deficient NSCLC causes sensitivities to CDK4/6 inhibitors, abemaciclib or palbociclib.

Melanoma [ICD-11: 2C30]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Cyclin-dependent kinase 4 (CDK4) [9]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Missense mutation; p.R24C (c.70C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin sample; N.A.
• Experiment for Molecule Alteration: Western blot analysis; Immunohistochemistry assay
• Experiment for Drug Resistance: SRB assay

References

• Ref 1: Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review .Int J Cancer. 2019 Sep 1;145(5):1179-1188. doi: 10.1002/ijc.32020. Epub 2019 Jan 7. 10.1002/ijc.32020
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