Reference Detail

Ref Type

Journal Article

PMID

(24265152)

Authors

Shi H, Hong A, Kong X, Koya RC, Song C, Moriceau G, Hugo W, Yu CC, Ng C, Chodon T, Scolyer RA, Kefford RF, Ribas A, Long GV, Lo RS

Title

A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	4	1	2014 Jan	69-79	Cancer Discov

URL

Abstract Text

BRAF inhibitor (BRAFi) therapy leads to remarkable anti melanoma responses, but the initial tumor shrinkage is commonly incomplete, providing a nidus for subsequent disease progression. Adaptive signaling may underlie early BRAFi resistance and influence the selection pattern for genetic variants, causing late, acquired resistance. We show here that BRAFi (or BRAFi + MEKi) therapy in patients frequently led to rebound phosphorylated AKT (p-AKT) levels in their melanomas early on-treatment. In cell lines, BRAFi treatment led to rebound levels of receptor tyrosine kinases (RTK; including PDGFRβ), phosphatidyl (3,4,5)-triphosphate (PIP3), pleckstrin homology domain recruitment, and p-AKT. PTEN expression limited this BRAFi-elicited PI3K-AKT signaling, which could be rescued by the introduction of a mutant AKT1 (Q79K) known to confer acquired BRAFi resistance. Functionally, AKT1(Q79K) conferred BRAFi resistance via amplification of BRAFi-elicited PI3K-AKT signaling. In addition, mitogen-activated protein kinase pathway inhibition enhanced clonogenic growth dependency on PI3K or AKT. Thus, adaptive or genetic upregulation of AKT critically participates in melanoma survival during BRAFi 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 V600X	melanoma	sensitive	Buparlisib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Buparlisib (BKM120) and Mekinist (trametinib) inhibited growth of BRAF V600-mutant melanoma cell lines in culture, with increased efficacy over either agent alone (PMID: 24265152).	24265152
BRAF V600X	melanoma	sensitive	Selumetinib + Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Selumetinib (AZD6244) and Zelboraf (vemurafenib) inhibited growth of BRAF V600-mutant melanoma cell lines in culture, with increased efficacy over either agent alone (PMID: 24265152).	24265152
BRAF V600X	melanoma	sensitive	Trametinib + Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Mekinist (trametinib) and Zelboraf (vemurafenib) inhibited growth of BRAF V600-mutant melanoma cell lines in culture, with increased efficacy over either agent alone (PMID: 24265152).	24265152
BRAF V600X	melanoma	sensitive	Buparlisib + Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Buparlisib (BKM120) and Zelboraf (vemurafenib) inhibited growth of BRAF V600-mutant melanoma cell lines in culture, with increased efficacy over either agent alone (PMID: 24265152).	24265152
BRAF V600X	melanoma	sensitive	MK2206 + Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of MK2206 and Zelboraf (vemurafenib) inhibited growth of BRAF V600-mutant melanoma cell lines in culture, with increased efficacy over either agent alone (PMID: 24265152).	24265152
BRAF V600X PTEN neg	melanoma	sensitive	Uprosertib	Preclinical - Cell culture	Actionable	In a preclinical study, lack of PTEN expression was associated with increased sensitivity to GSK2141795 in BRAF V600-mutant melanoma cell lines in culture (PMID: 24265152).	24265152
BRAF V600X	melanoma	sensitive	Buparlisib + Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Buparlisib (BKM120) and Koselugo (selumetinib) inhibited growth of BRAF V600-mutant melanoma cell lines in culture, with increased efficacy over either agent alone (PMID: 24265152).	24265152
BRAF V600X	melanoma	sensitive	MK2206 + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of MK2206 and Mekinist (trametinib) inhibited growth of BRAF V600-mutant melanoma cell lines in culture, with increased efficacy over either agent alone (PMID: 24265152).	24265152