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

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

Author information

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.

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.

PMID:
26365186
DOI:
10.1016/j.celrep.2015.08.037
[Indexed for MEDLINE]
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