Treatment of BRAF(V600E) mutant melanoma by small molecule drugs that target the BRAF or MEK kinases can be effective, but resistance develops invariably1,2. In contrast, colon cancers that harbour the same BRAF(V600E) mutation are intrinsically resistant to BRAF inhibitors, due to feedback activation of the epidermal growth factor receptor (EGFR)3,4. Here we show that 6 out of 16 melanoma tumours analysed acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Using a chromatin-regulator-focused short hairpin RNA (shRNA) library, we find that suppression of sex determining region Y-box 10 (SOX10) in melanoma causes activation of TGF-β signalling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-β (PDGFRB), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-β results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-β becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells having varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug, but this is reversed when the drug treatment is discontinued. We find evidence for SOX10 loss and/or activation of TGF-β signalling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Our findings provide a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a ‘drug holiday’ and identify patients with EGFR-positive melanoma as a group that may benefit from re-treatment after a drug holiday.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Gene Expression Omnibus
RNA sequencing data are available at Gene Expression Omnibus with accession code GSE50535.
We thank the NKI Core Facilities for Genomics and Molecular Pathology & Biobanking for tumour tissue and support in DNA sequencing. We thank S. Roy for collecting clinical data and N. Kamsu Kom for tissue preparation. This work was supported by grants from the European Research Council (ERC), the Dutch Cancer Society (KWF), the EU COLTHERES project and grants by the Netherlands Organization for Scientific Research (NWO) to Cancer Genomics Netherlands (CGC.NL). Additional support was provided by Fondazione Piemontese per la Ricerca sul Cancro—ONLUS grant ‘Farmacogenomica—5 per mille 2009 MIUR’ (F.D.N.); AIRC MFAG 11349 (F.D.N.); AIRC IG grant n. 12812 (A.B.); and Canadian Institutes of Health Research (CIHR) grant MOP-130540 (S.Hu).
Extended data figures
This table contains patient information.
A list of genes in chromatin library.
Top hits from genetic screen.
RNAseq data from shSOX10 cells.
Gene Set Enrichment Analysis of SOX10 regulated genes.
shRNA IDs and sequences.
List of QRT-PCR primers used.