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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Bibliographic Details
Published in:Cell reports (Cambridge) Vol. 12; no. 12; pp. 1978 - 1985
Main Authors: 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
Language:English
Published: United States Elsevier Inc 29.09.2015
Elsevier
Subjects:
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
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Summary: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.
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2015.08.037