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Nature. 2014 Apr 3;508(7494):118-22. doi: 10.1038/nature13121. Epub 2014 Mar 26.

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

Author information

1
1] Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands [2].
2
1] Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands [2] Department of Biochemistry, The Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3G 1Y6, Canada [3].
3
Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
4
Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France.
5
Division of Medical Oncology, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
6
Division of Pathology, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
7
1] Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands [2] Department of Pathology, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
8
1] University of Torino, Department of Oncology, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy [2] Candiolo Cancer Institute - FPO, IRCCS, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy.
9
Candiolo Cancer Institute - FPO, IRCCS, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy.
10
1] University of Torino, Department of Oncology, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy [2] Candiolo Cancer Institute - FPO, IRCCS, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy [3] FIRC Institute of Molecular Oncology (IFOM), 20139 Milano, Italy.

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.

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PMID:
24670642
DOI:
10.1038/nature13121
[Indexed for MEDLINE]

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