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
Affiliations
Shivshankari Rajkumar
Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada
Diana Berry
Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada
Kayla A. Heney
Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada
Colton Strong
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
LeeAnn Ramsay
Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada
Mathieu Lajoie
Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada
Rached Alkallas
Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada
Tan-Trieu Nguyen
Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada
Cameron Thomson
University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
Mozhdeh Ahanfeshar-Adams
Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada
Matthew Dankner
Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, QC H4A 3J1, Canada
Teresa Petrella
Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
April A.N. Rose
Department of Oncology, McGill University, Montréal, QC H4A 3T2, Canada; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montréal, QC H3T 1E2, Canada
Peter M. Siegel
Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Department of Medicine, McGill University, Montréal, QC H4A 3J1, Canada
Ian R. Watson
Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Research Institute of the McGill University Health Centre, Montréal, QC H3H 2R9, Canada; Corresponding author
Summary: 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.
