Abstract 4524: Combined inhibition of PIM and PI3 kinases shows an enhanced efficacy in a number of solid tumour cell lines

Abstract

Abstract Introduction: PIM kinases play an important role in a number of aspects of the regulation of cell cycle and proliferation. Over expression of PIM kinases is associated with oncogenicity in a number of haematological and solid tumours. Recent evidencesuggests that PIM expression is upregulated by inhibition of signalling on the AKT/PI3K/mTOR pathway. We set out to examine the effects of inhibition of PIM kinases in a number of solid tumor cell lines and to explore the effects of concomitant inhibition of the AKT/PI3K/mTOR pathway with novel agents having dual PIM kinase and PI3k inhibition. Representative cell lines for colorectal, lung, oesophageal and prostate tumors (HCT116, A549 and H460, OE21, PC3 respectively) were chosen for testing in a cytotoxicity assay. Compounds tested were GDC-0941, a prototypical PI3K inhibitor, AZD 1208, a pan-PIM inhibitor (i.e. equi-active on all 3 PIM isoforms), IBL- 201 and IBL-202 (dual-acting PI3K/PIM inhibitors) and IBL-301 and IBL-302 (triple-acting PI3K/PIM/mTOR inhibitors). Rapamycin the prototypical mTOR inhibitor and cisplatin were also tested as reference compounds. Results: The pan-PIM compound AZD1208 showed efficacy in all cell lines in the micromolar range. Rapamycin was also active across similar concentrations. GDC-0941, the PI3K inhibitor exhibited moderate efficacy across the cell line panel . The dual and triple inhibitors showed cytotoxic effects at sub micromolar concentrations, with the OE21 and PC3 oesophageal and prostate lines respectively showing the most sensitive responses. Conclusion: These results suggest that in selected solid tumor cell lines combined inhibition of PIM and PI3 kinases can lead to an increased cytotoxic effect. Further studies are under way to determine if this observation is corroborated in vivo. Combined inhibition of PIM and PI3 kinases with a single molecule may offer significant opportunities in the clinic for efficacy in key tumour subsets and to circumvent acquired resistance via feedback mechanisms. Citation Format: Michael O'Neil, C. Blanco Aparicio, S. Jiang, S. Martinez, A. McKenzie, Martin Page, J. Pastor. Combined inhibition of PIM and PI3 kinases shows an enhanced efficacy in a number of solid tumour cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4524. doi:10.1158/1538-7445.AM2014-4524