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

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 journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	1978-85
Number of pages	8
Journal	Cell Reports [E]
Volume	12
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2015.08.037
Publication status	Published - 29 Sept 2015

Access to Document

10.1016/j.celrep.2015.08.037

PTPN11Final published version, 2.4 MB

Cite this

@article{740672b0174f48568bcf88879da4f476,

title = "PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs",

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.",

author = "Anirudh Prahallad and Heynen, {Guus J J E} and Giovanni Germano and Willems, {Stefan M} and Bastiaan Evers and Loredana Vecchione and Valentina Gambino and Cor Lieftink and Beijersbergen, {Roderick L} and {Di Nicolantonio}, Federica and Alberto Bardelli and Rene Bernards",

year = "2015",

month = sep,

day = "29",

doi = "10.1016/j.celrep.2015.08.037",

language = "English",

volume = "12",

pages = "1978--85",

journal = "Cell Reports [E]",

issn = "2211-1247",

publisher = "Cell Press",

number = "12",

}

TY - JOUR

T1 - PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs

AU - Prahallad, Anirudh

AU - Heynen, Guus J J E

AU - Germano, Giovanni

AU - Willems, Stefan M

AU - Evers, Bastiaan

AU - Vecchione, Loredana

AU - Gambino, Valentina

AU - Lieftink, Cor

AU - Beijersbergen, Roderick L

AU - Di Nicolantonio, Federica

AU - Bardelli, Alberto

AU - Bernards, Rene

PY - 2015/9/29

Y1 - 2015/9/29

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2015.08.037

DO - 10.1016/j.celrep.2015.08.037

M3 - Article

C2 - 26365186

SN - 2211-1247

VL - 12

SP - 1978

EP - 1985

JO - Cell Reports [E]

JF - Cell Reports [E]

IS - 12

ER -

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

Abstract

Access to Document

Fingerprint

Cite this