Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF-mutant lung cancer.
Oncogenic activation of protein kinase BRAF drives tumor growth by promoting mitogen-activated protein kinase (MAPK) pathway signaling. Because oncogenic mutations in BRAF occur in ∼2-7% of lung adenocarcinoma (LA), BRAF-mutant LA is the most frequent cause of BRAF-mutant cancer mortality worldwide. Whereas most tumor types harbor predominantly the BRAFV600E-mutant allele, the spectrum of BRAF mutations in LA includes BRAFV600E(∼60% of cases) and non-V600E mutant alleles (∼40% of cases) such as BRAFG469Aand BRAFG466VThe presence of BRAFV600Ein LA has prompted clinical trials testing selective BRAF inhibitors such as vemurafenib in BRAFV600E-mutant patients. Despite promising clinical efficacy, both innate and acquired resistance often result from reactivation of MAPK pathway signaling, thus limiting durable responses to the current BRAF inhibitors. Further, the optimal therapeutic strategy to block non-V600E BRAF-mutant LA remains unclear. Here, we report the efficacy of the Raf proto-oncogene serine/threonine protein kinase (RAF) inhibitor, PLX8394, that evades MAPK pathway reactivation in BRAF-mutant LA models. We show that PLX8394 treatment is effective in both BRAFV600Eand certain non-V600 LA models, in vitro and in vivo. PLX8394 was effective against treatment-naive BRAF-mutant LAs and those with acquired vemurafenib resistance caused by an alternatively spliced, truncated BRAFV600Ethat promotes vemurafenib-insensitive MAPK pathway signaling. We further show that acquired PLX8394 resistance occurs via EGFR-mediated RAS-mTOR signaling and is prevented by upfront combination therapy with PLX8394 and either an EGFR or mTOR inhibitor. Our study provides a biological rationale and potential polytherapy strategy to aid the deployment of PLX8394 in lung cancer patients.
Department of Medicine, University of California, San Francisco, CA 94158.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.|Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158.
Ross A
RA
Okimoto
Department of Medicine, University of California, San Francisco, CA 94158.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.
Luping
L
Lin
Department of Medicine, University of California, San Francisco, CA 94158.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.|Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158.
Victor
V
Olivas
Department of Medicine, University of California, San Francisco, CA 94158.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.|Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158.
Elton
E
Chan
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.
Evan
E
Markegard
Plexxikon Inc., Berkeley, CA 94710.
Andrey
A
Rymar
Department of Medicine, University of California, San Francisco, CA 94158.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.|Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158.
Dana
D
Neel
Department of Medicine, University of California, San Francisco, CA 94158.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.
Xiao
X
Chen
Department of Medicine, University of California, San Francisco, CA 94158.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.|Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158.
Golzar
G
Hemmati
Plexxikon Inc., Berkeley, CA 94710.
Gideon
G
Bollag
Department of Medicine, University of California, San Francisco, CA 94158; trever.bivona@ucsf.edu.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.|Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158.
Trever G
TG
Bivona
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D006574:Heterocyclic Compounds, 2-Ring / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D006574:Heterocyclic Compounds, 2-Ring; C000715470:MAS1 protein, human; C000602642:PLX8394; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D013449:Sulfonamides; C482119:BRAF protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D048493:Proto-Oncogene Proteins B-raf
BRAF; cancer; lung; targeted therapy