Abstract
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.
Highlights
Half of all malignant melanomas harbor an activating mutation in the serine/threonine kinase BRAF; ~90% of these mutations involve a valine to glutamic acid substitution at residue 600 (V600E) [1]
To assess whether hepatocyte growth factor (HGF) could rescue BRAFV600E mutant melanoma cells from BRAF inhibition, three cell lines were treated with vemurafenib in the presence or absence of HGF
To determine the prevalence of HGF rescue, 14 BRAFV600E mutant melanoma cell lines were treated with a dose titration matrix of vemurafenib and HGF (Supplementary Figure 1A)
Summary
Half of all malignant melanomas harbor an activating mutation in the serine/threonine kinase BRAF; ~90% of these mutations involve a valine to glutamic acid substitution at residue 600 (V600E) [1]. Combined treatment with a MEK inhibitor and pharmacologic inhibition, or small interfering RNA knockdown of the implicated RTKs, resulted in synergistic effects on TNBC cell line viability These findings highlight a compensatory role for growth factors and their accompanying RTKs in reactivating MAPK pathway signaling and conveying resistance to downstream targeted therapy. In this manuscript we report findings that provide further insight into the mechanism of HGF-mediated rescue of BRAF or MEK inhibition in BRAFV600E mutant melanoma and demonstrate that MET and GAB1 (a key adaptor protein in HGF/MET signaling) are uniquely upregulated following MAPK pathway inhibition. These findings add significant and novel mechanistic insight into the potential role of HGF/MET signaling in mediating resistance to BRAF and MEK inhibitors and support the clinical evaluation of MET kinase inhibitors and HGF-neutralizing antibodies in melanoma
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