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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 |
| Molecular Profile | Protein Effect | Treatment Approaches |
|---|---|---|
| CDKN2A loss | loss of function | CDK Inhibitor (Pan) CDK4 Inhibitor CDK4/6 Inhibitor CDK6 Inhibitor |
| CDKN2A loss NRAS mut | ||
| CDKN2A loss NRAS Q61K | ||
| CDKN2A loss PIK3CA act mut | ||
| CDKN2A loss PIK3CA E545K PIK3CA amp | ||
| CDKN2A loss PIK3CA E542K PIK3CA amp |
| 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | lung non-small cell carcinoma | sensitive | Palbociclib | Phase II | Actionable | In a Phase II trial (TAPUR), Ibrance (palbociclib) treatment resulted in a disease control rate of 29% (7/28, 1 partial response, 6 stable disease at 16 weeks) in patients with non-small cell lung cancer harboring CDKN2A loss or mutations, with a median progression-free survival of 9.7 weeks and a median overall survival of 20.6 months (J Clin Oncol 37, 2019 (suppl; abstr 9041); NCT02693535). | detail... |
| CDKN2A loss | lung non-small cell carcinoma | sensitive | Palbociclib | Phase II | Actionable | In a Phase II trial, treatment with Ibrance (palbociclib) resulted in and 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 | 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 | 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 | 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 | 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 | 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 NRAS mut | melanoma | sensitive | Abemaciclib | Phase I | Actionable | In a Phase I trial, Abemaciclib (LY2835219) resulted in a partial response in a melanoma patient with CDKN2A loss and NRAS mutation (PMID: 27217383). | detail... 27217383 |
| CDKN2A loss NRAS Q61K | melanoma | sensitive | SBI-0640756 | Preclinical | Actionable | In a preclinical study, SBI-0640726 delayed tumor growth of melanomas in mice with a genetic background of NRAS Q61K and CDKN2A loss (PMID: 26603897). | 26603897 |
| CDKN2A loss NRAS Q61K | melanoma | sensitive | Palbociclib + Trametinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination of Ibrance (palbociclib) and Mekinist (trametinib) induced tumor regression in a mouse melanoma model expressing NRAS Q61K and harboring CDKN2A loss (PMID: 22983396). | 22983396 |
| CDKN2A loss PIK3CA act mut | lung squamous cell carcinoma | predicted - sensitive | Buparlisib + Palbociclib | Preclinical - Pdx | Actionable | In a preclinical study, treatment with the combination of Buparlisib (BYL719) and Ibrance (palbociclib) resulted in increased tumor growth inhibition compared to either agent alone in patient-derived xenograft (PDX) models of lung squamous cell carcinoma harboring PIK3CA E542K or E545K mutations with p16 (CDKN2A) loss, including models that also had either PIK3CA amplification or PTEN loss (PMID: 30093452). | 30093452 |
| CDKN2A loss PIK3CA E545K PIK3CA amp | lung squamous cell carcinoma | sensitive | Buparlisib + Palbociclib | Preclinical - Pdx | Actionable | In a preclinical study, treatment with the combination of Buparlisib (BYL719) and Ibrance (palbociclib) resulted in increased tumor growth inhibition compared to either agent alone in patient-derived xenograft (PDX) models of lung squamous cell carcinoma harboring PIK3CA E545K and PIK3CA amplification, with p16 (CDKN2A) loss (PMID: 30093452). | 30093452 |
| CDKN2A loss PIK3CA E542K PIK3CA amp | lung squamous cell carcinoma | sensitive | Buparlisib + Palbociclib | Preclinical - Pdx | Actionable | In a preclinical study, treatment with the combination of Buparlisib (BYL719) and Ibrance (palbociclib) resulted in increased tumor growth inhibition compared to either agent alone in a patient-derived xenograft (PDX) model of lung squamous cell carcinoma harboring PIK3CA E542K and PIK3CA amplification, with p16 (CDKN2A) loss (PMID: 30093452). | 30093452 |