Abstract
Acquired EGFR expression confers BRAF inhibitor resistance in BRAF-mutant melanoma.
Major finding: Acquired EGFR expression confers BRAF inhibitor resistance in BRAF-mutant melanoma.
Concept: SOX10 downregulation promotes EGFR activation and proliferation only in the presence of drug.
Impact: Melanomas with EGFR-driven BRAF inhibitor resistance may regain sensitivity after a drug holiday.
Targeting BRAF or MEK in BRAFV600E-mutant melanoma is often effective, but acquired resistance remains a major clinical hurdle. Increased activation of receptor tyrosine kinases such as EGF receptor (EGFR) has been linked to intrinsic and acquired BRAF inhibitor resistance. Sun and colleagues found that 6 of 16 BRAFV600E-mutant melanoma biopsies obtained after the development of BRAF or MEK inhibitor resistance showed increased EGFR expression compared with matched pretreatment samples. Overexpression of EGFR in treatment-naïve melanoma cell lines reduced growth in vitro and in vivo concomitant with features of oncogene-induced senescence, suggesting that EGFR activation only confers a selective advantage in the presence of BRAF or MEK inhibitors. Although prolonged treatment of BRAF-mutant melanoma cells in vitro with the BRAF inhibitor vemurafenib did not promote high EGFR expression, strongly EGFR-positive cells were enriched when cells were infected with a library of small hairpin RNAs targeting chromatin regulators and selected for vemurafenib resistance, but only knockdown of SRY (sex determining region Y)-box 10 (SOX10) consistently induced EGFR upregulation. SOX10 depletion, like EGFR overexpression, reduced melanoma cell proliferation and increased markers of oncogene-induced senescence but promoted proliferation in the presence of vemurafenib. Mechanistically, SOX10 depletion activated TGFβ signaling, which in turn induced expression of EGFR. EGFR inhibition alone could not reverse vemurafenib resistance induced by SOX10 loss, indicating that EGFR is not the sole driver of drug resistance, but combined inhibition of BRAF and PI3K restored growth inhibition in SOX10-depleted cells. Notably, acquired EGFR expression was only advantageous during BRAF or MEK inhibitor treatment, as high EGFR expression was selected against upon removal of drug. Collectively, these data indicate that EGFR activation is part of an adaptive response to BRAF/MEK inhibition in melanomas and raise the possibility that patients with drug-resistant melanomas with acquired EGFR expression may regain sensitivity following a drug holiday.
