Reference Detail

Ref Type

Journal Article

PMID

(20531415)

Authors

Paraiso KH, Fedorenko IV, Cantini LP, Munko AC, Hall M, Sondak VK, Messina JL, Flaherty KT, Smalley KS

Title

Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
British journal of cancer	102	12	2010 Jun 08	1724-30	Br J Cancer

URL

Abstract Text

Resistance to BRAF inhibitors is an emerging problem in the melanoma field. Strategies to prevent and overcome resistance are urgently required.The dynamics of cell signalling, BrdU incorporation and cell-cycle entry after BRAF inhibition was measured using flow cytometry and western blot. The ability of combined BRAF/MEK inhibition to prevent the emergence of resistance was demonstrated by apoptosis and colony formation assays and in 3D organotypic cell culture.BRAF inhibition led to a rapid recovery of phospho-ERK (pERK) signalling. Although most of the cells remained growth arrested in the presence of drug, a minor population of cells retained their proliferative potential and escaped from BRAF inhibitor therapy. A function for the rebound pERK signalling in therapy escape was demonstrated by the ability of combined BRAF/MEK inhibition to enhance the levels of apoptosis and abrogate the onset of resistance.Combined BRAF/MEK inhibition may be one strategy to prevent the emergence of drug resistance in BRAF-V600E-mutated melanomas.

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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	melanoma	sensitive	BI-69A11	Preclinical	Actionable	In a preclinical study, BI-69A11 inhibited proliferation and Akt/mTOR signaling in human melanoma cell lines harboring BRAF V600E in culture (PMID: 26603897, PMID: 20531415).	20531415 26603897
BRAF V600E	melanoma	sensitive	SBI-0640756	Preclinical	Actionable	In a preclinical study, SBI-0640756 inhibited proliferation and Akt/mTOR signaling in human melanoma cell lines harboring BRAF V600E in culture (PMID: 26603897, PMID: 20531415).	20531415 26603897
BRAF V600E	melanoma	sensitive	SBI-0640726	Preclinical	Actionable	In a preclinical study, SBI-0640726 inhibited proliferation and Akt/mTOR signaling in human melanoma cell lines harboring BRAF V600E in culture (PMID: 26603897, PMID: 20531415).	20531415 26603897