Molecular mechanisms of resistance to BRAF and MEK inhibitors in BRAFV600E non-small cell lung cancer.

Abstract

INTRODUCTION:

BRAF is a confirmed therapeutic target in non-small cell lung cancer (NSCLC), as the BRAF inhibitor dabrafenib, in combination with the MEK inhibitor trametinib, is approved for the treatment of NSCLC harbouring BRAF V600E mutation. Scant evidence is available concerning the mechanisms of resistance to BRAF/MEK inhibitors in BRAFV600E NSCLC.

PATIENTS AND METHODS:

Patients with BRAFV600E NSCLC with acquired resistance to BRAF/MEK inhibitors were included in the institutional, prospective MATCH-R (from "Matching Resistance") trial and underwent tumour and liquid biopsies at the moment of radiological progression. Extensive molecular analyses were performed, including targeted next-generation sequencing (NGS), whole-exome sequencing (WES), RNA sequencing and comparative genomic hybridisation (CGH) array.

RESULTS:

Of the 11 patients included, eight had progressed on dabrafenib-trametinib combination, two on dabrafenib monotherapy and one on vemurafenib (BRAF inhibitor). Complete molecular analyses were available for seven patients, whereas an additional case had only targeted NGS and CGH array data. Among these eight patients, acquired molecular events potentially responsible for resistance were detected in three who progressed on dabrafenib-trametinib combination, that is, MEK1 K57N, RAS viral (v-ras) oncogene homolog (NRAS) Q61R and rat sarcoma viral oncogene homolog (KRAS) Q61R mutations. One patient progressing on dabrafenib monotherapy developed a PTEN frameshift mutation. No molecular hints addressing resistance emerged in the remaining four patients with analyses performed. Tumour mutational burden, evaluated by WES in seven patients, was low (median = 2.06 mutations/megabase, range = 1.57-3.75 mut/Mb).

CONCLUSIONS:

Novel resistance mechanisms to BRAF/MEK inhibitors in BRAFV600E NSCLC were identified, pointing out the recurring involvement of the MAPK pathway and guiding the development of new treatment strategies.

• Authors: Francesco Facchinetti, Ludovic Lacroix, Laura Mezquita, Jean-Yves Scoazec, Yohann Loriot, Lambros Tselikas, Anas Gazzah, Etienne Rouleau, Julien Adam, Stefan Michiels, Christophe Massard, Fabrice André, Ken A Olaussen, Gilles Vassal, Karen Howarth, Benjamin Besse, Jean-Charles Soria, Luc Friboulet, David Planchard
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 132 Pg. 211-223 (06 2020) ISSN: 1879-0852 [Electronic] England
• PMID: 32388065 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• MAP Kinase Kinase Kinases

Topics

• Adult
• Aged
• Aged, 80 and over
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Drug Resistance, Neoplasm (genetics)
• Female
• Follow-Up Studies
• Humans
• Lung Neoplasms (drug therapy, genetics, pathology)
• MAP Kinase Kinase Kinases (antagonists & inhibitors)
• Male
• Middle Aged
• Mutation
• Prognosis
• Prospective Studies
• Protein Kinase Inhibitors (therapeutic use)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics)