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

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 phosph...

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Veröffentlicht in:	Cell reports (Cambridge) Jg. 12; H. 12; S. 1978 - 1985
Hauptverfasser:	Prahallad, Anirudh, Heynen, Guus J.J.E., Germano, Giovanni, Willems, Stefan M., Evers, Bastiaan, Vecchione, Loredana, Gambino, Valentina, Lieftink, Cor, Beijersbergen, Roderick L., Di Nicolantonio, Federica, Bardelli, Alberto, Bernards, Rene
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Elsevier Inc 29.09.2015 Elsevier
Schlagworte:	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 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 ras Proteins - genetics ras Proteins - metabolism Receptor, Epidermal Growth Factor - genetics Receptor, Epidermal Growth Factor - metabolism RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Sulfonamides - pharmacology Transduction, Genetic Xenograft Model Antitumor Assays
ISSN:	2211-1247, 2211-1247
Online-Zugang:	Volltext
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Zusammenfassung:	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. [Display omitted] •PTPN11 inhibition is synthetic lethal with BRAF inhibitors in BRAF mutant colon cancer•PTPN11 inhibition blocks the effects of EGFR activation by BRAF inhibitors•PTPN11 inhibition is lethal to cancers with activated RTKs•Phosphorylation of PTPN11 is a biomarker of RTK-driven drug resistance in melanoma Using a synthetic lethality screen, Prahallad et al. report that PTPN11 suppression enhances the response to BRAF inhibition in BRAF mutant colon cancers by preventing the effects of receptor tyrosine kinase reactivation. These findings identify PTPN11 as a drug target to combat both intrinsic and acquired resistance to targeted cancer drugs.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2015.08.037