Activation of pim kinases is sufficient to promote resistance to MET small-molecule inhibitors

Ningfei An, Ying Xiong, Amanda C. LaRue, Andrew Kraft, Bo Cen

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Mesenchymal-epithelial transition (MET) blockade offers a new targeted therapy particularly in those cancers with MET amplification. However, the efficacy and the duration of the response to MET inhibitors are limited by the emergence of drug resistance. Here, we report that resistance to small-molecule inhibitors of MET can arise from increased expression of the prosurvival Pim protein kinases. This resistance mechanism was documented in non-small cell lung cancer and gastric cancer cells with MET amplification. Inhibition of Pim kinases enhanced cell death triggered by short-term treatment with MET inhibitors. Pim kinases control the translation of anti-apoptotic protein Bcl-2 at an internal ribosome entry site and this mechanism was identified as the basis for Pim-mediated resistance to MET inhibitors. Protein synthesis was increased in drug-resistant cells, secondary to a Pim-mediated increase in cap-independent translation. In cells rendered drug resistant by chronic treatment with MET inhibitors, genetic or pharmacologic inhibition of Pim kinases was sufficient to restore sensitivity in vitro and in vivo. Taken together, our results rationalize Pim inhibition as a strategy to augment responses and blunt acquired resistance to MET inhibitors in cancer.

Original languageEnglish (US)
Pages (from-to)5318-5328
Number of pages11
JournalCancer Research
Volume75
Issue number24
DOIs
StatePublished - Dec 15 2015

Fingerprint

Epithelial-Mesenchymal Transition
Stomach Neoplasms
proto-oncogene proteins pim
Apoptosis Regulatory Proteins
Drug Resistance
Non-Small Cell Lung Carcinoma
Pharmaceutical Preparations
Protein Kinases
Neoplasms
Cell Death

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Activation of pim kinases is sufficient to promote resistance to MET small-molecule inhibitors. / An, Ningfei; Xiong, Ying; LaRue, Amanda C.; Kraft, Andrew; Cen, Bo.

In: Cancer Research, Vol. 75, No. 24, 15.12.2015, p. 5318-5328.

Research output: Contribution to journalArticle

An, Ningfei ; Xiong, Ying ; LaRue, Amanda C. ; Kraft, Andrew ; Cen, Bo. / Activation of pim kinases is sufficient to promote resistance to MET small-molecule inhibitors. In: Cancer Research. 2015 ; Vol. 75, No. 24. pp. 5318-5328.
@article{83b5dd57aa334a12834a68e5b8e9f132,
title = "Activation of pim kinases is sufficient to promote resistance to MET small-molecule inhibitors",
abstract = "Mesenchymal-epithelial transition (MET) blockade offers a new targeted therapy particularly in those cancers with MET amplification. However, the efficacy and the duration of the response to MET inhibitors are limited by the emergence of drug resistance. Here, we report that resistance to small-molecule inhibitors of MET can arise from increased expression of the prosurvival Pim protein kinases. This resistance mechanism was documented in non-small cell lung cancer and gastric cancer cells with MET amplification. Inhibition of Pim kinases enhanced cell death triggered by short-term treatment with MET inhibitors. Pim kinases control the translation of anti-apoptotic protein Bcl-2 at an internal ribosome entry site and this mechanism was identified as the basis for Pim-mediated resistance to MET inhibitors. Protein synthesis was increased in drug-resistant cells, secondary to a Pim-mediated increase in cap-independent translation. In cells rendered drug resistant by chronic treatment with MET inhibitors, genetic or pharmacologic inhibition of Pim kinases was sufficient to restore sensitivity in vitro and in vivo. Taken together, our results rationalize Pim inhibition as a strategy to augment responses and blunt acquired resistance to MET inhibitors in cancer.",
author = "Ningfei An and Ying Xiong and LaRue, {Amanda C.} and Andrew Kraft and Bo Cen",
year = "2015",
month = "12",
day = "15",
doi = "10.1158/0008-5472.CAN-15-0544",
language = "English (US)",
volume = "75",
pages = "5318--5328",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "24",

}

TY - JOUR

T1 - Activation of pim kinases is sufficient to promote resistance to MET small-molecule inhibitors

AU - An, Ningfei

AU - Xiong, Ying

AU - LaRue, Amanda C.

AU - Kraft, Andrew

AU - Cen, Bo

PY - 2015/12/15

Y1 - 2015/12/15

N2 - Mesenchymal-epithelial transition (MET) blockade offers a new targeted therapy particularly in those cancers with MET amplification. However, the efficacy and the duration of the response to MET inhibitors are limited by the emergence of drug resistance. Here, we report that resistance to small-molecule inhibitors of MET can arise from increased expression of the prosurvival Pim protein kinases. This resistance mechanism was documented in non-small cell lung cancer and gastric cancer cells with MET amplification. Inhibition of Pim kinases enhanced cell death triggered by short-term treatment with MET inhibitors. Pim kinases control the translation of anti-apoptotic protein Bcl-2 at an internal ribosome entry site and this mechanism was identified as the basis for Pim-mediated resistance to MET inhibitors. Protein synthesis was increased in drug-resistant cells, secondary to a Pim-mediated increase in cap-independent translation. In cells rendered drug resistant by chronic treatment with MET inhibitors, genetic or pharmacologic inhibition of Pim kinases was sufficient to restore sensitivity in vitro and in vivo. Taken together, our results rationalize Pim inhibition as a strategy to augment responses and blunt acquired resistance to MET inhibitors in cancer.

AB - Mesenchymal-epithelial transition (MET) blockade offers a new targeted therapy particularly in those cancers with MET amplification. However, the efficacy and the duration of the response to MET inhibitors are limited by the emergence of drug resistance. Here, we report that resistance to small-molecule inhibitors of MET can arise from increased expression of the prosurvival Pim protein kinases. This resistance mechanism was documented in non-small cell lung cancer and gastric cancer cells with MET amplification. Inhibition of Pim kinases enhanced cell death triggered by short-term treatment with MET inhibitors. Pim kinases control the translation of anti-apoptotic protein Bcl-2 at an internal ribosome entry site and this mechanism was identified as the basis for Pim-mediated resistance to MET inhibitors. Protein synthesis was increased in drug-resistant cells, secondary to a Pim-mediated increase in cap-independent translation. In cells rendered drug resistant by chronic treatment with MET inhibitors, genetic or pharmacologic inhibition of Pim kinases was sufficient to restore sensitivity in vitro and in vivo. Taken together, our results rationalize Pim inhibition as a strategy to augment responses and blunt acquired resistance to MET inhibitors in cancer.

UR - http://www.scopus.com/inward/record.url?scp=84955474409&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84955474409&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-15-0544

DO - 10.1158/0008-5472.CAN-15-0544

M3 - Article

C2 - 26670562

AN - SCOPUS:84955474409

VL - 75

SP - 5318

EP - 5328

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 24

ER -