PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs

Anirudh Prahallad; Guus J J E Heynen; Giovanni Germano; Stefan M Willems; Bastiaan Evers; Loredana Vecchione; Valentina Gambino; Cor Lieftink; Roderick L Beijersbergen; Federica Di Nicolantonio; Alberto Bardelli; Rene Bernards

doi:10.1016/j.celrep.2015.08.037

PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs

Cell Rep. 2015 Sep 29;12(12):1978-85. doi: 10.1016/j.celrep.2015.08.037. Epub 2015 Sep 10.

Affiliations

¹ Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
² 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.
³ 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.
⁴ 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.
⁵ Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address: r.bernards@nki.nl.

PMID: 26365186
DOI: 10.1016/j.celrep.2015.08.037

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Colonic Neoplasms / drug therapy*
Colonic Neoplasms / genetics
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology
Drug Resistance, Neoplasm / drug effects*
Drug Resistance, Neoplasm / genetics
ErbB Receptors / genetics
ErbB Receptors / metabolism
Gene Expression Regulation, Neoplastic*
Genetic Vectors
Genomic Library
High-Throughput Nucleotide Sequencing
Humans
Indoles / pharmacology
Lentivirus / genetics
MAP Kinase Signaling System
Melanoma / drug therapy*
Melanoma / genetics
Melanoma / metabolism
Melanoma / pathology
Mice
Mice, Inbred NOD
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics*
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
Proto-Oncogene Proteins B-raf / genetics
Proto-Oncogene Proteins B-raf / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Sulfonamides / pharmacology
Transduction, Genetic
Vemurafenib
Xenograft Model Antitumor Assays
ras Proteins / genetics
ras Proteins / metabolism

Substances

Antineoplastic Agents
Indoles
RNA, Small Interfering
Sulfonamides
Vemurafenib
EGFR protein, human
ErbB Receptors
BRAF protein, human
Proto-Oncogene Proteins B-raf
PTPN11 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 11
ras Proteins