Platinum-based
chemotherapy is widely used to treat various
cancers, but many patients ultimately relapse due to drug resistance. We employed phosphoproteomic analysis and functional assays of the response of SK-OV-3
ovarian cancer cells to
cisplatin as a strategy to identify
kinases as candidate druggable targets to sensitize cells to
platinum. A SILAC-based approach combined with TiO2-based
phosphopeptide enrichment allowed the direct identification of ERK1/2, p90RSK, and ERBB2 as
kinases whose phosphorylation is regulated by
cisplatin. Bioinformatic analysis revealed enrichment in linear phosphorylation motifs predicted to be targets of p38MAPK, CDK2, and PIM2. All three
PIM kinases were found expressed in a panel of 10
ovarian cancer cell lines, with the oncogenic PIM2 being the most commonly induced by
cisplatin. Targeting PIM2
kinase by either biochemical inhibitors or RNA interference impaired cell growth, decreased
cisplatin-triggered BAD phosphorylation, and sensitized
ovarian cancer cells to drug-induced apoptosis. Overexpression of PIM2 triggered anchorage-independent growth and resulted in increased BAD phosphorylation and cell resistance to
DNA damaging agents. The data show that the PIM2
kinase plays a role in the response of
ovarian cancer cells to
platinum drugs and suggest that PIM inhibitors may find clinical application as an adjunct to
platinum-based
therapies.