MAPK pathway inhibition induces MET and GAB1 levels, priming BRAF mutant melanoma for rescue by hepatocyte growth factor
Metrics: PDF 1362 views | HTML 1510 views | ?
Sean Caenepeel1, Keegan Cooke1, Sarah Wadsworth1, Guo Huang1, Lidia Robert2, Blanca Homet Moreno2, Giulia Parisi2, Elaina Cajulis1, Richard Kendall1, Pedro Beltran1, Antoni Ribas2, Angela Coxon1, Paul E. Hughes1
1Department of Oncology Research, Amgen, Inc., Thousand Oaks, CA, USA
2Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA
Paul E. Hughes, email: email@example.com
Keywords: melanoma, resistance, BRAF, HGF, MET
Received: October 21, 2016 Accepted: January 16, 2017 Published: January 27, 2017
Therapeutic resistance is a major obstacle to achieving durable clinical responses with targeted therapies, highlighting a need to elucidate the underlying mechanisms responsible for resistance and identify strategies to overcome this challenge. An emerging body of data implicates the tyrosine kinase MET in mediating resistance to BRAF inhibitors in BRAFV600E mutant melanoma. In this study we observed a dominant role for the HGF/MET axis in mediating resistance to BRAF and MEK inhibitors in models of BRAFV600E and NRAS mutant melanoma. In addition, we showed that MAPK pathway inhibition induced rapid increases in MET and GAB1 levels, providing novel mechanistic insight into how BRAFV600E mutant melanoma is primed for HGF-mediated rescue. We also determined that tumor-derived HGF, not systemic HGF, may be required to convey resistance to BRAF inhibition in vivo and that resistance could be reversed following treatment with AMG 337, a selective MET inhibitor. In summary, these findings support the clinical evaluation of MET-directed targeted therapy to circumvent resistance to BRAF and MEK inhibitors in BRAFV600E mutant melanoma. In addition, the induction of MET following treatment with BRAF and MEK inhibitors has the potential to serve as a predictive biomarker for identifying patients best suited for MET inhibitor combination therapy.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.