Reference Detail

Ref Type

Journal Article

PMID

(33953400)

Authors

Yen I, Shanahan F, Lee J, Hong YS, Shin SJ, Moore AR, Sudhamsu J, Chang MT, Bae I, Dela Cruz D, Hunsaker T, Klijn C, Liau NPD, Lin E, Martin SE, Modrusan Z, Piskol R, Segal E, Venkatanarayan A, Ye X, Yin J, Zhang L, Kim JS, Lim HS, Kim KP, Kim YJ, Han HS, Lee SJ, Kim ST, Jung M, Hong YH, Noh YS, Choi M, Han O, Nowicka M, Srinivasan S, Yan Y, Kim TW, Malek S

Title

ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature	594	7863	2021 Jun	418-423	Nature

URL

Abstract Text

Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAFV600-mutant melanoma, they are ineffective in non-BRAFV600 mutant cells1-3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAFV600E- and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of belvarafenib in BRAFV600E- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with belvarafenib, we identified new recurrent mutations in ARAF within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors.

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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
Belvarafenib	Belvarafenib	17	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Belvarafenib		HM95573\|GDC-5573\|RO7223619	RAF Inhibitor (Pan) 28	Belvarafenib (HM95573) selectively inhibits RAF dimer formation, leading to inhibition of ARAF, BRAF, and CRAF activity, and potentially resulting in tumor growth inhibition (PMID: 33953400).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
BRAF	G534D	missense	unknown	BRAF G534D lies within the protein kinase domain of the Braf protein (UniProt.org). G534D has been demonstrated to confer resistance to Raf inhibitors in culture (PMID: 33953400), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Mar 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF G534D NRAS Q61L	melanoma	resistant	Belvarafenib	Preclinical - Cell culture	Actionable	In a preclinical study, expression of BRAF G534D in a melanoma cell line harboring NRAS Q61L conferred resistance to treatment with Belvarafenib (HM95573) in culture (PMID: 33953400).	33953400
NRAS Q61L	melanoma	sensitive	Belvarafenib + Cobimetinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the addition of Cotellic (cobimetinib) to treatment with Belvarafenib (HM95573) in melanoma cell lines harboring NRAS Q61L resulted in greater inhibition of cell proliferation in culture compared to single agent alone, and led to decreased tumor volume, with increased efficacy and response durability in a cell line xenograft model (PMID: 33953400).	33953400
BRAF V600D	melanoma	sensitive	Belvarafenib + Cobimetinib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Cotellic (cobimetinib) to treatment with Belvarafenib (HM95573) in a melanoma cell line harboring BRAF V600D resulted in greater inhibition of cell proliferation in culture compared to single agent alone (PMID: 33953400).	33953400
NRAS Q61R	melanoma	predicted - sensitive	Belvarafenib	Case Reports/Case Series	Actionable	In a Phase I trial, Belvarafenib (HM95573) treatment in a melanoma patient harboring NRAS Q61R led to a tumor reduction of 84% after 24 weeks of treatment and a confirmed partial response at 12 weeks, and response to treatment was maintained for 40 weeks (PMID: 33953400; NCT03118817).	33953400
BRAF V600E	melanoma	predicted - sensitive	Belvarafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Belvarafenib (HM95573) treatment led to inhibition of tumor growth in a melanoma cell line xenograft model harboring BRAF V600E (PMID: 33953400).	33953400
BRAF V600E	colorectal cancer	predicted - sensitive	Belvarafenib	Case Reports/Case Series	Actionable	In a Phase I trial, Belvarafenib (HM95573) treatment in a colorectal cancer patient harboring BRAF V600E led to a tumor reduction of 39% after 8 weeks of treatment and a confirmed partial response at 12 weeks, and response to treatment was maintained for 8 weeks (PMID: 33953400; NCT03118817).	33953400
NRAS Q61R	Advanced Solid Tumor	sensitive	Belvarafenib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing NRAS Q61R were sensitive to treatment with Belvarafenib (HM95573) in culture, demonstrating decreased cell viability (PMID: 33953400).	33953400
NRAS Q61K	melanoma	predicted - sensitive	Belvarafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Belvarafenib (HM95573) treatment led to inhibition of tumor growth in a melanoma cell line xenograft model harboring NRAS Q61K (PMID: 33953400).	33953400