Reference Detail

Ref Type

Journal Article

PMID

(24265154)

Authors

Wagle N, Van Allen EM, Treacy DJ, Frederick DT, Cooper ZA, Taylor-Weiner A, Rosenberg M, Goetz EM, Sullivan RJ, Farlow DN, Friedrich DC, Anderka K, Perrin D, Johannessen CM, McKenna A, Cibulskis K, Kryukov G, Hodis E, Lawrence DP, Fisher S, Getz G, Gabriel SB, Carter SL, Flaherty KT, Wargo JA, Garraway LA

Title

MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	4	1	2014 Jan	61-8	Cancer Discov

URL

Abstract Text

Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP-ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (MEK2(Q60P)). MEK2(Q60P) conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal-regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.

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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
CBL	P201S	missense	unknown	CBL P201S lies within the Cbl-PTB domain of the Cbl protein (UniProt.org). P201S has been identified in sequencing studies (PMID: 25303977, PMID: 24265154), but has not been biochemically characterized and therefore, its effect on Cbl protein function is unknown (PubMed, Feb 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E MAP2K1 P162S	melanoma	sensitive	Dabrafenib + Trametinib	Preclinical	Actionable	In a preclinical study, the combination of Mekinist (trametinib) and Tafinlar (dabrafenib) inhibited growth of BRAF V600E-mutant melanoma cells expressing MAP2K1 P162S in culture (PMID: 24265154).	24265154
BRAF V600E MAP2K1 P162S	melanoma	sensitive	Trametinib	Preclinical	Actionable	In a preclinical study, Mekinist (trametinib) inhibited growth of BRAF V600E-mutant melanoma cells expressing MAP2K1 P162S in culture (PMID: 24265154).	24265154
BRAF V600E MAP2K1 P162S	melanoma	sensitive	Dabrafenib	Preclinical	Actionable	In a preclinical study, Tafinlar (dabrafenib) inhibited growth of BRAF V600E-mutant melanoma cells expressing MAP2K1 P162S in culture (PMID: 24265154).	24265154
BRAF V600E MAP2K1 C121S	melanoma	resistant	Dabrafenib + Trametinib	Preclinical	Actionable	In a preclinical study, MAP2K1 C121S conferred resistance to the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) in BRAF V600E-mutant melanoma cells in culture (PMID: 24265154).	24265154
BRAF V600E MAP2K1 G128V	melanoma	conflicting	Dabrafenib + Trametinib	Preclinical	Actionable	In a preclinical study, MAP2K1 G128V conferred resistance to the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) in BRAF V600E-mutant melanoma cells in culture (PMID: 24265154).	24265154