title: PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs.
abstract: Most BRAF (V600E) mutant melanomas are sensitive to selective BRAF inhibitors, but BRAF mutant colon cancers are intrinsically resistant to these drugs because of feedback activation of EGFR. We performed an RNA-interference-based genetic screen in BRAF mutant colon cancer cells to search for phosphatases whose knockdown induces sensitivity to BRAF inhibition. We found that suppression of protein tyrosine phosphatase non-receptor type 11 (PTPN11) confers sensitivity to BRAF inhibitors in colon cancer. Mechanistically, we found that inhibition of PTPN11 blocks signaling from receptor tyrosine kinases (RTKs) to the RAS-MEK-ERK pathway. PTPN11 suppression is lethal to cells that are driven by activated RTKs and prevents acquired resistance to targeted cancer drugs that results from RTK activation. Our findings identify PTPN11 as a drug target to combat both intrinsic and acquired resistance to several targeted cancer drugs. Moreover, activated PTPN11 can serve as a biomarker of drug resistance resulting from RTK activation.
authors.affiliation: 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: 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: Candiolo Cancer Institute - FPO, IRCCS, Str. prov. 142 Km 3.95, 10060 Candiolo, Torino, Italy; FIRC Institute of Molecular Oncology (IFOM), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Germano
authors.affiliation: Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; 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: Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Evers
authors.affiliation: Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Loredana
authors.initials: L
authors.lastname: Vecchione
authors.affiliation: Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Valentina
authors.initials: V
authors.lastname: Gambino
authors.affiliation: 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: 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: Candiolo Cancer Institute - FPO, IRCCS, Str. prov. 142 Km 3.95, 10060 Candiolo, Torino, Italy; Department of Oncology, University of Torino, Str. prov. 142 Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Str. prov. 142 Km 3.95, 10060 Candiolo, Torino, Italy; Department of Oncology, University of Torino, Str. prov. 142 Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address: r.bernards@nki.nl.
authors.forename: Rene
authors.initials: R
authors.lastname: Bernards
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D015698:Genomic Library; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D016086:Lentivirus / Q000235:genetics; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014161:Transduction, Genetic; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D034741:RNA, Small Interfering; D013449:Sulfonamides; D000077484:Vemurafenib; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D018631:ras Proteins