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ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma

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Abstract
Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAF(V600)-mutant melanoma, they are ineffective in non-BRAF(V600) mutant cells(1-3). Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAF(V600E)- 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 BRAF(V600E)- 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.
Author(s)
김규표김승태김유정김진수김태원노영수이수정임형석정민규최문정한혜숙홍윤희Avinashnarayan VenkatanarayanIvana YenJianping YinLiangxuan ZhangMalgorzata NowickaOakpil HanShiva MalekShrividhya SrinivasanXin YeYibing YanFrances Shanahan이지윤홍용상신상준Amanda R MooreJawahar Sudh
Issued Date
2021
Type
Article
Keyword
AnimalsAntimitotic agentsAntineoplastic agentsCell LineCell LineTumorDosage and administrationDrug ResistanceNeoplasm - drug effectsDrug ResistanceNeoplasm - geneticsDrug therapyFemaleGenetic aspectsHealth aspectsHumansMelanomaMelanoma - drug therapyMelanoma - geneticsMelanoma - pathologyMiceMutationMutation (Biology)Physiological aspectsProtein kinasesProtein Multimerization - drug effectsProto-Oncogene Proteins A-raf - antagonists & inhibitorsProto-Oncogene Proteins A-raf - chemistryProto-Oncogene Proteins A-raf - geneticsraf Kinases - antagonists & inhibitorsraf Kinases - chemistry
DOI
10.1038/s41586-021-03515-1
URI
https://oak.ulsan.ac.kr/handle/2021.oak/8036
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_proquest_miscellaneous_2522620963&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,ARAF%20mutations%20confer%20resistance%20to%20the%20RAF%20inhibitor%20belvarafenib%20in%20melanoma&offset=0&pcAvailability=true
Publisher
NATURE
Location
영국
Language
영어
ISSN
0028-0836
Citation Volume
594
Citation Number
7863
Citation Start Page
418
Citation End Page
418
Appears in Collections:
Medicine > Medicine
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