Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma.

Abstract

Treatment of BRAF(V600E) mutant melanoma by small molecule drugs that target the BRAF or MEK kinases can be effective, but resistance develops invariably. 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). 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.

• Authors: Chong Sun, Liqin Wang, Sidong Huang, Guus J J E Heynen, Anirudh Prahallad, Caroline Robert, John Haanen, Christian Blank, Jelle Wesseling, Stefan M Willems, Davide Zecchin, Sebastijan Hobor, Prashanth K Bajpe, Cor Lieftink, Christina Mateus, Stephan Vagner, Wipawadee Grernrum, Ingrid Hofland, Andreas Schlicker, Lodewyk F A Wessels, Roderick L Beijersbergen, Alberto Bardelli, Federica Di Nicolantonio, Alexander M M Eggermont, Rene Bernards
• Journal: Nature (Nature) Vol. 508 Issue 7494 Pg. 118-22 (Apr 03 2014) ISSN: 1476-4687 [Electronic] England
• PMID: 24670642 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Indoles
• Protein Kinase Inhibitors
• RNA, Small Interfering
• SOX10 protein, human
• SOXE Transcription Factors
• Sulfonamides
• Transforming Growth Factor beta
• Vemurafenib
• ErbB Receptors
• Receptor Protein-Tyrosine Kinases
• Receptor, Platelet-Derived Growth Factor beta
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Mitogen-Activated Protein Kinase Kinases

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Cell Proliferation (drug effects)
• Cellular Senescence (drug effects)
• Drug Resistance, Neoplasm (drug effects, genetics)
• ErbB Receptors (biosynthesis, genetics, metabolism)
• Female
• Flow Cytometry
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Library
• Humans
• Indoles (administration & dosage, pharmacology)
• Melanoma (drug therapy, enzymology, genetics, pathology)
• Mice
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, metabolism)
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics, metabolism)
• RNA, Small Interfering
• Receptor Protein-Tyrosine Kinases (biosynthesis, genetics, metabolism)
• Receptor, Platelet-Derived Growth Factor beta (biosynthesis, genetics, metabolism)
• SOXE Transcription Factors (deficiency, genetics)
• Signal Transduction (drug effects)
• Sulfonamides (administration & dosage, pharmacology)
• Transforming Growth Factor beta (metabolism, pharmacology)
• Vemurafenib