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

doi:10.1016/j.celrep.2022.110634

Melanomas with concurrent BRAF non-p.V600 and NF1 loss-of-function mutations are targetable by BRAF/MEK inhibitor combination therapy

Cell Rep. 2022 Apr 5;39(1):110634. doi: 10.1016/j.celrep.2022.110634.

Authors

Affiliations

¹ Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada.
² Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
³ Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada.
⁴ Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada.
⁵ University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
⁶ Goodman Cancer Institute, McGill University, Montréal, QC H3A 1A3, Canada; Department of Medicine, McGill University, Montréal, QC H4A 3J1, Canada.
⁷ Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada.
⁸ Department of Oncology, McGill University, Montréal, QC H4A 3T2, Canada; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montréal, QC H3T 1E2, Canada.
⁹ 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.
¹⁰ 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. Electronic address: [email protected].

PMID: 35385748
DOI: 10.1016/j.celrep.2022.110634

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Melanoma* / drug therapy
Melanoma* / genetics
Mitogen-Activated Protein Kinase Kinases / genetics
Mutation / genetics
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins B-raf / genetics
Skin Neoplasms* / drug therapy
Skin Neoplasms* / genetics

Substances

Protein Kinase Inhibitors
BRAF protein, human
Proto-Oncogene Proteins B-raf
Mitogen-Activated Protein Kinase Kinases

Associated data

ClinicalTrials.gov/NCT03839342
ClinicalTrials.gov/NCT03843775

Grants and funding

PJT-152975/CIHR/Canada