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

Research output: Contribution to journalArticle

58 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1978-1985
Number of pages8
JournalCell Reports
Volume12
Issue number12
DOIs
Publication statusPublished - Sep 29 2015

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Non-Receptor Type 11 Protein Tyrosine Phosphatase
Receptor Protein-Tyrosine Kinases
Colonic Neoplasms
Pharmaceutical Preparations
Chemical activation
Neoplasms
Drug Receptors
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Biomarkers
RNA Interference
Phosphoric Monoester Hydrolases
Drug Resistance
Protein-Tyrosine Kinases
Melanoma
Cells
RNA
Feedback

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Prahallad, A., Heynen, G. J. J. E., Germano, G., Willems, S. M., Evers, B., Vecchione, L., ... Bernards, R. (2015). PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs. Cell Reports, 12(12), 1978-1985. https://doi.org/10.1016/j.celrep.2015.08.037

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

In: Cell Reports, Vol. 12, No. 12, 29.09.2015, p. 1978-1985.

Research output: Contribution to journalArticle

Prahallad, A, Heynen, GJJE, Germano, G, Willems, SM, Evers, B, Vecchione, L, Gambino, V, Lieftink, C, Beijersbergen, RL, Di Nicolantonio, F, Bardelli, A & Bernards, R 2015, 'PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs', Cell Reports, vol. 12, no. 12, pp. 1978-1985. https://doi.org/10.1016/j.celrep.2015.08.037
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. / PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs. In: Cell Reports. 2015 ; Vol. 12, No. 12. pp. 1978-1985.
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