Abstract 2915: PIM kinase inhibition blocks activation of mTOR pathway components and enhances rapamycin-mediated tumor growth inhibition in prostate cancers

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Constitutive activation of the phosphatidylinositol 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathway due to the loss of the PTEN tumor suppressor is a common event in advanced prostate cancers. However, mTOR inhibitors have failed to demonstrate objective therapeutic responses in prostate cancer patients. We hypothesize that the serine/threonine PIM kinases provide an alternate survival signal that bypasses mTOR pathway inhibition in prostate cancers. Thus far, there are no published studies investigating the influence of PIM kinases on mTOR pathway inhibition in solid tumors. Since the PIM kinases are upregulated in advanced prostate cancers and co-operate with several key signal transduction pathways, such as those regulated by the c-Myc oncogene, we suggest that simultaneous inhibition of both PIM and mTOR kinases may result in improved clinical outcomes. We demonstrate that ectopic expression of PIM1 kinase results in ∼10-fold decrease in sensitivity to the prototype mTOR inhibitor, rapamycin, in prostate cancer cells. Resistance to rapamycin with PIM1 overexpression is associated with activation of multiple targets downstream of mTOR as well as those mTOR complex components that are not efficiently inhibited by rapamycin. These observations suggest that PIM kinase inhibition may be a viable strategy to overcome resistance to rapamycin in prostate cancers. In line with this idea, we show that PIM kinase inhibition with a small molecule inhibitor (Supergen, Inc.) restricts the growth of a wide variety of prostate cancer cells and suppresses the activation of mTOR pathway components that are insensitive to rapamycin. Interestingly, when the PIM kinase inhibitor is combined with rapamycin, we observe an enhanced inhibition of tumor cell viability in vitro and superior anti-tumor activity in vivo in subcutaneously implanted Myc-driven prostate cancers as compared to single agents alone. Combination treatment in Myc-driven prostate cancer cells results in a greater inhibition of c-Myc protein expression and a heightened level of apoptosis as demonstrated by increased expression of the cleaved PARP (poly(ADP-ribose) polymerase) protein in a time and dose-dependent manner, suggesting a mechanism for this combination therapy. Furthermore, evaluation of the mTOR pathway components reveals that this combination therapy inhibits the activation of a greater number of targets as compared to individual agents alone. Ongoing studies aim to dissect the mechanism of this novel combination treatment in prostate cancers. Overall, our data indicate that PIM kinase activity contributes towards limiting mTOR pathway inhibition in prostate cancers and that the simultaneous inhibition of both the mTOR and PIM kinase pathways can be developed as a novel therapeutic combination strategy for treating advanced stage prostate cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2915. doi:10.1158/1538-7445.AM2011-2915