Melanomas with concurrent BRAF non-p.V600 and NF1 loss-of-function mutations are targetable by BRAF/MEK inhibitor combination therapy
Shivshankari Rajkumar, Diana Berry, Kayla A Heney, Colton Strong, LeeAnn Ramsay, Mathieu Lajoie, Rached Alkallas, Tan-Trieu Nguyen, Cameron Thomson, Mozhdeh Ahanfeshar-Adams, Matthew Dankner, Teresa Petrella, April A N Rose, Peter M Siegel, Ian R Watson, Shivshankari Rajkumar, Diana Berry, Kayla A Heney, Colton Strong, LeeAnn Ramsay, Mathieu Lajoie, Rached Alkallas, Tan-Trieu Nguyen, Cameron Thomson, Mozhdeh Ahanfeshar-Adams, Matthew Dankner, Teresa Petrella, April A N Rose, Peter M Siegel, Ian R Watson
Abstract
Although combination BRAF/MEK inhibition has produced significant survival benefits for BRAF p.V600 mutant melanomas, targeted therapies approved for BRAF non-p.V600 mutant melanomas remain limited. Through the analysis of 772 cutaneous melanoma exomes, we reveal that BRAF non-p.V600 mutations co-occurs more frequently with NF1 loss, but not with oncogenic NRAS mutations, than expected by chance. We present cell signaling data, which demonstrate that BRAF non-p.V600 mutants can signal as monomers and dimers within an NF1 loss context. Concordantly, BRAF inhibitors that inhibit both monomeric and dimeric BRAF synergize with MEK inhibition to significantly reduce cell viability in vitro and tumor growth in vivo in BRAF non-p.V600 mutant melanomas with co-occurring NF1 loss-of-function mutations. Our data suggest that patients harboring BRAF non-p.V600 mutant melanomas may benefit from current FDA-approved BRAF/MEK inhibitor combination therapy currently reserved for BRAF p.V600 mutant patients.
Trial registration: ClinicalTrials.gov NCT03839342 NCT03843775.
Keywords: CP: Cancer; cell signaling; drug targets; kinase; melanoma; tumor suppressor.
Conflict of interest statement
Declaration of interests I.R.W. reports grants from Canadian Institutes of Health Research (grant #PJT-152975), the Melanoma Research Alliance (grant #412429), and the Canada Research Chairs Program. I.R.W. also reports collaboration with KEW, Inc. outside the submitted work. T.P. has received funding from Novartis and Roche and has also received honoraria from and has been on advisory boards for Novartis, BMS, Merck, Sunpharma, Sanofi, and Pfizer.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Source: PubMed