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 antiapoptotic 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.
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina. The Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Ningfei
authors.initials: N
authors.lastname: An
authors.affiliation: The Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: The Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina. Research Services, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: LaRue
authors.affiliation: University of Arizona Cancer Center, Tucson, Arizona. cen@musc.edu akraft@uacc.arizona.edu.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Kraft
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina. The Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina. cen@musc.edu akraft@uacc.arizona.edu.
authors.forename: Bo
authors.initials: B
authors.lastname: Cen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000201:enzymology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim