Abstract 1732: PI3K inhibition potentiates ABT-737 induced apoptosis in colorectal cancer cells independent of MCL1 downregulation or AKT/mTOR inhibition.

Abstract

Abstract Background Colorectal cancer (CRC) is the third most common cancer and is a leading cause of morbidity worldwide. The five year survival rate of patients with advanced or metastatic CRC is less than 5%, identifying the need for new and improved therapies in the treatment of advanced and metastatic CRC. Phosphoinositide 3-kinase (PI3K) signaling has been implicated in several hallmarks of cancer, such as sustained proliferation, resisting cell death and invasion, and is frequently deregulated in CRC via a mutation of effectors such as PIK3CA, PIK3R1 and PTEN, making it an attractive therapeutic drug target. Despite this, inhibition of PI3K signaling does not cause cell death in CRC cells. Furthermore, CRC cells are relatively resistant to the BH3 mimetic ABT-737, which directly targets the BCL2 family of proteins inducing apoptosis via the mitochondrial pathway. Therefore, we investigated whether combining PI3K inhibitors and ABT-737 in CRC cells might synergise to induce apoptosis. Results PI3K inhibition enhanced ABT-737 induced apoptosis by 2.3-4.5 fold and reduced expression levels of Mcl-1, an established resistance biomarker for ABT-737. PI3K inhibition enhanced ABT-737-induced apoptosis a further 1.4-2.4 fold in CRC cells with siRNA depleted Mcl-1 suggesting contributory mechanisms additional to Mcl-1 down regulation. PI3K inhibition increased levels of Bcl-xL bound BimEL independently of Mcl-1 depletion. Further investigations are being carried out to determine whether this is the cause of increase ABT-737 sensitivity. ABT-737-induced apoptosis was unaffected by inhibition of PI3K downstream effectors AKT and mTOR. A siRNA library screen has been conducted to identify proteins downstream of PI3K which affect ABT-737 sensitivity and the results will be reported. Conclusions These data reveal a PI3K inhibition enhanced, ABT-737 driven apoptosis that occurs via Mcl-1, AKT and mTOR independent mechanism(s) consistent with increased association of BimEL and Bcl-xL. Further work is ongoing to elucidate the molecular mechanisms that underpin enhanced response to this BH-3 mimetic in CRC. Citation Format: Danielle S. Potter, Paul J. Kelly, Olive A. Denneny, Caroline Dive, Christopher J. Morrow. PI3K inhibition potentiates ABT-737 induced apoptosis in colorectal cancer cells independent of MCL1 downregulation or AKT/mTOR inhibition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1732. doi:10.1158/1538-7445.AM2013-1732