Abstract 3257: Targeting small cell lung cancer harboringPIK3CAmutation with a selective oral PI3K inhibitor, PF-4989216.

Aberrant PI3K/AKT signaling occurs commonly in cancer. Gene mutation, amplification, and copy number gains in the catalytic p110α of PI3K have been shown in a variety of human cancers. Tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) dephosphorylates the 3-phosphoinositides and is frequently mutated, deleted, or down-regulated in many human cancers to constitutively activate the PI3K pathway. Small cell lung cancer (SCLC) patients have poor prognosis; response to second-line chemotherapy for patients with refractory disease is less than 10%, and survival is 3-4 months. Multiple phase III trials have been conducted, however the survival of SCLC patients has not significantly improved over the years. In this study, we characterized a selective PI3K inhibitor, PF-4989216, in preclinical SCLC models to investigate whether targeting the PI3K pathway may be a potential therapy for SCLC. PF-4989216 inhibits phosphorylation of PI3K downstream molecules and subsequently leads to induction in apoptosis and cell cycle block, as well as inhibition of cell proliferation, transformation, and xenograft tumor growth in SCLCs harboring a PIK3CA mutation. Moreover, our results suggest that there may be different mechanisms of tumorigenesis between PIK3CA mutation and PTEN loss in SCLCs, and indicate that PF-4989216 is a potential cancer drug candidate for small-cell lung cancer patients harboring a PIK3CA mutation. Citation Format: Marlena Walls, Sangita M. Baxi, Pramod P. Mehta, Elizabeth Epps, Heather Estrella, Kevin KC Liu, JinJiang Zhu, Chunze Li, Tod Smeal, Min-Jean Yin. Targeting small cell lung cancer harboring PIK3CA mutation with a selective oral PI3K inhibitor, PF-4989216. [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 3257. doi:10.1158/1538-7445.AM2013-3257