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Gene | CDKN2A |
Variant | loss |
Impact List | unknown |
Protein Effect | loss of function |
Gene Variant Descriptions | CDKN2A loss indicates loss of the CDKN2A gene, mRNA and protein. |
Associated Drug Resistance | |
Category Variants Paths |
CDKN2A mutant CDKN2A inact mut CDKN2A loss |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
CDKN2A loss | melanoma | sensitive | Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, a melanoma cell line with CDKN2A loss demonstrated sensitivity to Mekinist (trametinib) in culture, resulting in inhibition of cell growth (PMID: 27488531). | 27488531 |
CDKN2A loss | melanoma | sensitive | Alvocidib | Preclinical | Actionable | In a preclinical study, melanoma cell lines with CDKN2A loss demonstrated a greater sensitivity to Alvocidib (flavopiridol) as compared to melanoma cell lines positive for CDKN2A (PMID: 12777976). | 12777976 |
CDKN2A loss | Advanced Solid Tumor | no benefit | Ribociclib | Clinical Study | Actionable | In a combined analysis of 2 clinical trials (DRUP, MoST), Ibrance (palbociclib) or Kisqali (ribociclib) monotherapy had limited efficacy and resulted in no objective responses, a 15% clinical benefit rate at 16 weeks, median progression-free survival of 4 mo, and median overall survival of 5 mo in previously treated advanced solid tumor patients (n=112) with CDKN2A loss, CDK4, CDK6, CCND1, CCND2, or CCND3 amplification, or inactivating SMARCA4 mutations (PMID: 37424386; NCT02925234, ACTRN12616000931471). | 37424386 |
CDKN2A loss | chordoma | sensitive | Abemaciclib | Preclinical - Cell culture | Actionable | In a preclinical study, Abemaciclib (LY2835219) inhibited growth of chordoma cell lines with CDKN2A loss and loss of p16 protein expression in culture (PMID: 26183925). | 26183925 |
CDKN2A loss | pancreatic cancer | no benefit | Palbociclib | Phase II | Actionable | In a Phase II trial (TAPUR), patients with pancreatic cancer harboring a CDKN2A mutation or loss of CDKN2A (n=10) did not demonstrate an objective response or stable disease at 16 weeks when treated with single therapy, Ibrance (palbociclib), demonstrating a median progression-free survival of 7.2 weeks and an overall survival of 12.4 weeks (JCO Precision Oncology, Aug 14, 2019; NCT02693535). | detail... |
CDKN2A loss | melanoma | resistant | Palbociclib | Preclinical - Cell culture | Actionable | In a preclinical study, a melanoma cell line deficient for CDKN2A demonstrated resistance to treatment with Ibrance (palbociclib) in culture (PMID: 27488531). | 27488531 |
CDKN2A loss | chordoma | sensitive | Palbociclib | Preclinical - Cell culture | Actionable | In a preclinical study, Ibrance (palbociclib) inhibited expression of phosphorylated Rb and growth of chordoma cell lines with CDKN2A loss and loss of p16 protein expression in culture (PMID: 26183925). | 26183925 |
CDKN2A loss | lung squamous cell carcinoma | predicted - sensitive | Palbociclib | Clinical Study - Cohort | Actionable | In a Phase II trial (NLMT), Ibrance (palbociclib) treatment resulted in an observed objective response rate (ORR) of 0% (0/19), durable clinical benefit rate (DCBR) of 22% (4/18), and medial progression-free survival (PFS) of 4.2 months in patients with lung squamous cell carcinoma harboring CDKN2A loss, with Bayesian estimated OR and DCBR of 3% and 24%, respectively, and Bayesian predictive probability of success for PFS >0.99 (PMID: 32669708, NCT02664935). | 32669708 |
CDKN2A loss | lung non-small cell carcinoma | predicted - sensitive | Palbociclib | Phase II | Actionable | In a Phase II trial (TAPUR), Ibrance (palbociclib) treatment resulted in a disease control rate of 31% with 1 partial response and 6 with stable disease at 16 weeks in patients with advanced or metastatic non-small cell lung cancer harboring CDKN2A loss or mutations (n=29), with a median progression-free survival of 8.1 weeks and a median overall survival of 21.6 weeks (PMID: 35050752; NCT02693535). | 35050752 |
CDKN2A loss | lung non-small cell carcinoma | predicted - sensitive | Palbociclib | Phase II | Actionable | In a Phase II trial, treatment with Ibrance (palbociclib) resulted in stable disease in 50% (8/16) of non-small cell lung cancer patients with CDKN2A loss (J Clin Oncol 32:5s, 2014 (suppl; abstr 8077)). | detail... |
CDKN2A loss | lung adenocarcinoma | predicted - sensitive | Palbociclib | Clinical Study - Cohort | Actionable | In a Phase II trial (NLMT), Ibrance (palbociclib) treatment resulted in an observed objective response rate (ORR) of 4% (1/27), durable clinical benefit rate (DCBR) of 27.5% (8/29), and medial progression-free survival (PFS) of 3.3 months in patients with lung adenocarcinoma harboring CDKN2A loss, with Bayesian estimated OR and DCBR of 6% and 29%, respectively, and Bayesian posterior probability for PFS of 0.69 (PMID: 32669708, NCT02664935). | 32669708 |
CDKN2A loss | renal cell carcinoma | sensitive | Palbociclib | Preclinical | Actionable | In a preclinical study, renal cell carcinoma cell lines with CDKN2A loss were sensitive to Palbociclib (PD-0332991) (PMID: 23898052). | 23898052 |
CDKN2A loss | biliary tract cancer | no benefit | Palbociclib | Phase II | Actionable | In a Phase II trial (TAPUR), patients with biliary cancer harboring a CDKN2A mutation or loss of CDKN2A (n=10) did not demonstrate an objective response or stable disease at 16 weeks when treated with single therapy, Ibrance (palbociclib), demonstrating a median progression-free survival of 7.3 weeks and an overall survival of 11.1 weeks (JCO Precision Oncology, Aug 14, 2019; NCT02693535). | detail... |
CDKN2A loss | Advanced Solid Tumor | no benefit | Palbociclib | Clinical Study | Actionable | In a combined analysis of 2 clinical trials (DRUP, MoST), Ibrance (palbociclib) or Kisqali (ribociclib) monotherapy had limited efficacy and resulted in no objective responses, a 15% clinical benefit rate at 16 weeks, median progression-free survival of 4 mo, and median overall survival of 5 mo in previously treated advanced solid tumor patients (n=112) with CDKN2A loss, CDK4, CDK6, CCND1, CCND2, or CCND3 amplification, or inactivating SMARCA4 mutations (PMID: 37424386; NCT02925234, ACTRN12616000931471). | 37424386 |
CDKN2A loss | pancreatic cancer | decreased response | Gemcitabine + Palbociclib | Preclinical | Actionable | In a preclinical study, Ibrance (palbociclib) antagonized the efficacy of Gemzar (gemcitabine) in pancreatic cancer cells with CDKN2A loss in culture (PMID: 25156567). | 25156567 |
CDKN2A loss | pancreatic cancer | decreased response | GSK461364 + Palbociclib | Preclinical | Actionable | In a preclinical study, Ibrance (palbociclib) antagonized the efficacy of GSK461364 in pancreatic cancer cells with CDKN2A loss in culture (PMID: 25156567). | 25156567 |
CDKN2A loss | pancreatic cancer | decreased response | HMN-214 + Palbociclib | Preclinical | Actionable | In a preclinical study, Ibrance (palbociclib) antagonized the activity of HMN-214 in pancreatic cancer cell lines with CDKN2A loss in culture (PMID: 25156567). | 25156567 |
CDKN2A loss | brain glioblastoma multiforme | sensitive | Milciclib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Milciclib (PHA-848125AC) resulted in tumor regression in glioma cell line xenograft models with CDKN2A loss (PMID: 23347136). | 23347136 |
CDKN2A loss | neuroendocrine tumor | sensitive | ZK 304709 | Preclinical | Actionable | In a preclinical study, an orthotopic mouse model treated with ZK 304709 demonstrated an 80% tumor growth reduction in neuroendocrine tumor cells with CDKN2A loss (PMID: 18829975). | 18829975 |
CDKN2A loss | Advanced Solid Tumor | predicted - sensitive | PF-00477736 + PF3644022 | Preclinical - Cell culture | Actionable | In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited growth of multiple cancer cell lines harboring CDKN2A loss and in Cdkn2a-depleted transformed cells in culture (PMID: 26140595). | 26140595 |
CDKN2A loss | melanoma | sensitive | Abemaciclib + unspecified PD-1 antibody | Preclinical | Actionable | In a preclinical study, treatment with the combination of Verzenio (abemaciclib) and an anti-PD-1 antibody resulted in inhibition of both intracranial and extracranial tumor growth and improved survival compared to monotherapy or vehicle control in syngeneic mouse models of melanoma with loss of CDKN2A (PMID: 37611074). | 37611074 |