MAPK pathway inhibition induces MET and GAB1 levels, priming BRAF mutant melanoma for rescue by hepatocyte growth factor.
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.
Department of Oncology Research, Amgen, Inc., Thousand Oaks, CA, USA.
Sean
S
Caenepeel
Department of Oncology Research, Amgen, Inc., Thousand Oaks, CA, USA.
Keegan
K
Cooke
Department of Oncology Research, Amgen, Inc., Thousand Oaks, CA, USA.
Sarah
S
Wadsworth
Department of Oncology Research, Amgen, Inc., Thousand Oaks, CA, USA.
Guo
G
Huang
Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
Lidia
L
Robert
Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
Blanca Homet
BH
Moreno
Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
Giulia
G
Parisi
Department of Oncology Research, Amgen, Inc., Thousand Oaks, CA, USA.
Elaina
E
Cajulis
Department of Oncology Research, Amgen, Inc., Thousand Oaks, CA, USA.
Richard
R
Kendall
Department of Oncology Research, Amgen, Inc., Thousand Oaks, CA, USA.
Pedro
P
Beltran
Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
Antoni
A
Ribas
Department of Oncology Research, Amgen, Inc., Thousand Oaks, CA, USA.
Angela
A
Coxon
Department of Oncology Research, Amgen, Inc., Thousand Oaks, CA, USA.
Paul E
PE
Hughes
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
C000609912:AMG 337; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001549:Benzamides; D004151:Dipeptides; C098587:GAB1 protein, human; C066855:HGF protein, human; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D013449:Sulfonamides; D014230:Triazoles; D000077484:Vemurafenib; D017228:Hepatocyte Growth Factor; C028342:compound 20; C506614:mirdametinib; D004159:Diphenylamine; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
BRAF; HGF; MET; melanoma; resistance