Abstract 4479: Targeting non-small cell lung cancer cells harboring a PIK3CA mutation by a novel and oral PI3K selective inhibitor, PF-4989216

Abstract

Abstract Aberrant phosphatidylinositol 3-kinase (PI3K)/AKT signaling occurs commonly in cancer. Gene mutation, amplification, and copy number gains of the PI3K catalytic subunit p110α have been shown in a variety of human cancers. The 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 cancers to constitutively activate the PI3K pathway. In response to activation, PI3Ks phosphorylate membrane phosphatidylinositides to generate phosphatidylinositol 3,4,5-triphosphate (PIP3); PIP3 serves as an secondary messenger activating AKT and 3’-phosphoinositide-dependent kinase-1 (PDK1). Phosphorylation of AKT at threonine-308 (T308) by PDK1 and serine-473 (S473) by mTORC2 fully activates the AKT pathway to regulate various cellular processes including cell growth, proliferation, survival, and metabolism. Several inhibitors targeting the PI3K pathway have been developed in preclinical discovery or clinical trials; however, a small molecule inhibitor has not yet been approved for cancer treatment. Most inhibitors have inhibitory activity against both PI3Ks and mTOR kinases. The mTORC1 and mTORC2 complexes control critical pathways regulating cell proliferation, apoptosis, angiogenesis, and metabolism through AKT-dependent and AKT-independent mechanisms. Therefore, agents targeting PI3K with additional mTOR kinase inhibitory activities may carry extra toxicity through the disruption of mTOR function in normal cells. To develop a drug selectively targeting PI3K, we have identified PF-4989216 as a novel potent and selective PI3K inhibitor. In this study, we describe the in vitro and in vivo anti-tumor activity of PF-4989216 in human non-small-cell lung cancer cells (NSCLCs). PF-4989216 inhibits the phosphorylation of PI3K downstream molecules and subsequently leads to inhibition in cell proliferation and xenograft tumor growth in NSCLCs harboring a PIK3CA mutation, including an erlotinib resistant line, NCI-H1975. Although PF-4989216 inhibits the phosphorylation of PI3K downstream molecules in the NSCLCs with PTEN loss (NCI-H1650), PF-4989216 does not sufficiently induce anti-tumor efficacy in NCI-H1650. Our results suggest that there may be a different tumorigenesis mechanism between PIK3CA mutation and PTEN loss in NSCLCs, and indicate that PF-4989216 is a potential cancer drug candidate for erlotinib resistant non-small-cell lung cancer patients with PIK3CA mutation. 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 4479. doi:10.1158/1538-7445.AM2011-4479