Abstract 3683: Targeting PIK3CA mutant breast cancer with the combination of PIK3CA-specific inhibitor, BYL719, and IGF1-R antibody, ganitumab

Abstract

Abstract Background: PI3K/AKT signaling is a critical growth and survival pathway in many human cancers. PI3Ks are lipid kinases that are important in controlling signaling pathways involved in cell proliferation, motility, cell death and cell invasion. The α isoform of PI3K (PIK3CA) is linked upstream mainly to receptor tyrosine kinases. Various solid tumor types such as colorectal cancers, gastric cancers, brain cancers, glioblastomas, breast and lung cancers have been found to contain gain-of-function mutations of PIK3CA. The existing scientific evidence strongly supports the concept of targeting PIK3CA in human cancers, especially those harboring PIK3CA mutations. Sustained PIK3CA inhibition may lead to aberrant RTK signaling to attenuate PIK3CA inhibition. IGF1R is a RTK commonly expressed in human neoplasia. Its signaling, primarily through AKT, has been implicated in tumor cell survival. Additionally, IGF1R/IRS signaling has been shown to be a feedback pathway to down-modulate mTOR inhibition by RAD001 in cancer cells. We speculate that the efficacy of PIK3CA inhibition might be enhanced if PIK3CA inhibitor is combined with a targeted agent against a key RTK in pAKT signaling. Methods: With pATK signaling closely linked to mTOR signaling, we set out to examine whether PIK3CA inhibition would also trigger IGF1-R/IRS signaling. In addition, we explored the combination of PIK3CA-specific inhibitor, BYL719, and a fully human antibody against IGF1-R, AMG 479 (ganitumab), preclinically against a PIK3CA mutant breast cancer model, MCF7. Results: Our data indicate that IGF1-R/IRS signaling is activated upon PIK3CA inhibition. BYL719 exhibited concentration-dependent tumor growth inhibition in vitro. Ganitumab alone had modest inhibitory activity. The combination of BYL719 and ganitumab inhibited MCF7 growth synergistically in vitro. This combination was further tested in an MCF7 xenograft in mice. BYL719 monotherapy resulted in tumor stasis. Ganitumab alone had marginal growth inhibition. The combination of BYL719 and ganitumab led to tumor regression. Further more, the combination of BYL719 and Ganitumumab lead to increased suppression of pS6RP in vivo. Conclusions: Our data suggest that the combination of BYL719 and ganitumab would act synergistically to inhibit PIK3CA mutant breast cancer cells by blocking two inter-connected pathways. The combination of BYL719 and ganitumab has now entered into clinical trial (NCT01708161). It represents a promising approach against PI3KCA mutant breast cancers. Citation Format: Z. Alexander Cao, Maria Pinzon-Ortiz, Yan Chen, Xiaoyan Li, Pedro J. Beltran, Jennifer Gansert, Malte Peters, Robert Schlegel, Karl M. Schumacher, Alan Huang. Targeting PIK3CA mutant breast cancer with the combination of PIK3CA-specific inhibitor, BYL719, and IGF1-R antibody, ganitumab. [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 3683. doi:10.1158/1538-7445.AM2014-3683