Reference Detail

Ref Type

Journal Article

PMID

(34376578)

Authors

Nassar KW, Hintzsche JD, Bagby SM, Espinoza V, Langouët-Astrié C, Amato CM, Chimed TS, Fujita M, Robinson W, Tan AC, Schweppe RE

Title

Targeting CDK4/6 represents a therapeutic vulnerability in acquired BRAF/MEK inhibitor resistant melanoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics			2021 Aug 10	2049-2060	Mol Cancer Ther

URL

Abstract Text

There is a clear need to identify targetable drivers of resistance and potential biomarkers for salvage therapy for melanoma patients refractory to the combination of BRAF and MEK inhibition. In the present study, we performed whole exome sequencing on BRAF-V600E mutant melanoma patient tumors refractory to the combination of BRAF/MEK inhibition and identified acquired oncogenic mutations in NRAS and loss of the tumor suppressor gene CDKN2A. We hypothesized the acquired resistance mechanisms to BRAF/MEK inhibition were reactivation of the MAPK pathway and activation of the cell cycle pathway, which can both be targeted pharmacologically with the combination of a MEK inhibitor (trametinib) and a CDK4/6 inhibitor (palbociclib). In vivo, we found that combination of CDK4/6 and MEK inhibition significantly decreased tumor growth in two BRAF/MEK inhibitor resistant patient derived xenograft models. In vitro, we observed that the combination of CDK4/6 and MEK inhibition resulted in synergy and significantly reduced cellular growth, promoted cell cycle arrest and effectively inhibited downstream signaling of MAPK and cell cycle pathways in BRAF inhibitor resistant cell lines. Knockdown of CDKN2A in BRAF inhibitor resistant cells increased sensitivity to CDK4/6 inhibition alone and in combination with MEK inhibition. A key implication of our study is that the combination of CDK4/6 and MEK inhibitors overcomes acquired resistance to BRAF/MEK inhibitors, and loss of CDKN2A may represent a biomarker of response to the combination. Inhibition of the cell cycle and MAPK pathway represents a promising strategy for patients with metastatic melanoma who are refractory to BRAF/MEK inhibitor therapy.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E NRAS Q61K	melanoma	resistant	Vemurafenib	Case Reports/Case Series	Actionable	In a clinical case study, a melanoma patient harboring BRAF V600E experienced progressive disease after response to treatment Zelboraf (vemurafenib), and was found to have acquired NRAS Q61K (PMID: 34376578).	34376578
BRAF V600E CDKN2A loss NRAS G12V	melanoma	predicted - sensitive	Palbociclib + Trametinib	Preclinical - Pdx	Actionable	In a preclinical study, combination treatment with Ibrance (palbociclib) and Mekinist (trametinib) led to inhibition of tumor growth in a patient-derived xenograft (PDX) model of melanoma harboring BRAF V600E, NRAS G12V, and CDKN2A copy number loss (PMID: 34376578).	34376578
BRAF V600E CDKN2A loss NRAS G12V	melanoma	predicted - sensitive	Palbociclib + Ulixertinib	Preclinical - Pdx	Actionable	In a preclinical study, combination treatment with Ibrance (palbociclib) and Ulixertinib (BVD-523) led to inhibition of tumor growth in a patient-derived xenograft (PDX) model of melanoma harboring BRAF V600E, NRAS G12V, and CDKN2A copy number loss (PMID: 34376578).	34376578
BRAF V600E CDKN2A loss NRAS G12V	melanoma	predicted - resistant	Cobimetinib + Vemurafenib	Case Reports/Case Series	Actionable	In a clinical case study, a melanoma patient harboring BRAF V600E experienced progressive disease after a response to combination therapy with Zelboraf (vemurafenib) and Cotellic (cobimetinib), likely due to acquisition of NRAS G12V and a loss of one copy of CDKN2A (PMID: 34376578).	34376578
BRAF V600E CDKN2A loss NRAS Q61K	melanoma	predicted - resistant	Cobimetinib + Vemurafenib	Case Reports/Case Series	Actionable	In a clinical case study, a melanoma patient harboring BRAF V600E and NRAS Q61K experienced progressive disease after a response to combination therapy with Zelboraf (vemurafenib) and Cotellic (cobimetinib), land was found to have acquired loss of CDKN2A (PMID: 34376578).	34376578