title: 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.affiliation: 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].
authors.forename: Chong
authors.initials: C
authors.lastname: Sun
authors.affiliation: 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].
authors.forename: Liqin
authors.initials: L
authors.lastname: Wang
authors.affiliation: 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].
authors.forename: Sidong
authors.initials: S
authors.lastname: Huang
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Guus J J E
authors.initials: GJ
authors.lastname: Heynen
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Anirudh
authors.initials: A
authors.lastname: Prahallad
authors.affiliation: Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.affiliation: Division of Medical Oncology, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: John
authors.initials: J
authors.lastname: Haanen
authors.affiliation: Division of Medical Oncology, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Blank
authors.affiliation: Division of Pathology, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Jelle
authors.initials: J
authors.lastname: Wesseling
authors.affiliation: 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.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Willems
authors.affiliation: 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.
authors.forename: Davide
authors.initials: D
authors.lastname: Zecchin
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Sebastijan
authors.initials: S
authors.lastname: Hobor
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Prashanth K
authors.initials: PK
authors.lastname: Bajpe
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Cor
authors.initials: C
authors.lastname: Lieftink
authors.affiliation: Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France.
authors.forename: Christina
authors.initials: C
authors.lastname: Mateus
authors.affiliation: Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France.
authors.forename: Stephan
authors.initials: S
authors.lastname: Vagner
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Wipawadee
authors.initials: W
authors.lastname: Grernrum
authors.affiliation: Division of Pathology, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hofland
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlicker
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Roderick L
authors.initials: RL
authors.lastname: Beijersbergen
authors.affiliation: 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: 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.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France.
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
authors.affiliation: Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Rene
authors.initials: R
authors.lastname: Bernards
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015723:Gene Library; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D055757:SOXE Transcription Factors / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; D013449:Sulfonamides; D016212:Transforming Growth Factor beta; D000077484:Vemurafenib; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases