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Clin Cancer Res. 2019 Sep 12. pii: clincanres.2779.2018. doi: 10.1158/1078-0432.CCR-18-2779. [Epub ahead of print]

Adaptive Resistance to Dual BRAF/MEK Inhibition in BRAF-Driven Tumors Through Autocrine FGFR Pathway Activation.

Author information

1
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.
2
Human Oncology & Pathogenesis, Memorial Sloan Kettering Cancer Center.
3
Medicine, Massachusetts General Hostpital.
4
Bioinformatics, Genentech, Inc.
5
Discovery Oncology, Genentech.
6
Discovery Oncology, Genentech, Inc.
7
Pathology, University of California, San Francisco.
8
Department of Internal Medicine, The Ohio State University Medical Center.
9
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute.
10
Human Oncology and Pathogenesis Program, MSKCC.
11
Oncology, Pfizer (United States).
12
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco Frank.Mccormick@ucsf.edu.
13
Massachusetts General Hospital Cancer Center.

Abstract

PURPOSE:

Combined mitogen-activated protein kinase (MAPK) pathway inhibition using dual BRAF and MEK inhibitors has prolonged the duration of clinical response in patients with BRAFV600E driven tumors compared to either agent alone. However, resistance frequently arises.

EXPERIMENTAL DESIGN:

We generated cell lines resistant to dual BRAF/MEK inhibition and utilized a pharmacological synthetic lethal approach to identify a novel, adaptive resistance mechanism mediated through the fibroblast growth factor receptor (FGFR) pathway.

RESULTS:

In response to drug treatment, transcriptional upregulation of FGF1 results in autocrine activation of FGFR, which sustains extracellular signal-regulated kinases (ERK) activation. FGFR inhibition overcomes resistance to dual BRAF/MEK inhibitors in both cell lines and patient derived xenograft (PDX) models. Abrogation of this bypass mechanism in the front-line setting enhances tumor killing and prevents the emergence of drug-resistant cells. Moreover, clinical data implicate serum FGF1 levels in disease prognosis.

CONCLUSIONS:

Taken together, these results describe a new, adaptive resistance mechanism that is more commonly observed in the context of dual BRAF/MEK blockade as opposed to single agent treatment and reveal the potential clinical utility of FGFR targeting agents in combination with BRAF and MEK inhibitors as a promising strategy to forestall resistance in a subset of BRAF-driven cancers.

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