Abstract C074: Preclinical study of antitumor effect of alpelisib combined with paclitaxel in gastric caner
Authors: Kim Ji-Won , Kim Kui-Jin , Sung Ji Hea , Suh Koung Jin , Lee Ji Yun , Kim Se Hyun , Kim Jin Won , Lee Jeong-Ok , Kim Yu Jung , Bang Soo-Mee , Kim Jee Hyun , Lee Jong Seok , Lee Keun-Wook 
Published: March 2020

Abstract
Background: PIK3CA, encoding p110α subunit of PI3K, is the third most frequently mutated gene in gastric cancer (GC): 9–13% of non-hypermutated tumors and 32% of hypermutated tumors. Thus, PI3K pathway could be a potential therapeutic target in GC. Nevertheless, only few studies have been conducted so far. Materials and Methods: This preclinical study aimed to investigate the anti-tumor effects of alpelisib (Novartis, Basel, Switzerland), a PI3K p110α-specific inhibitor, using in vitro and in vivo models of GC. The combinatorial effects of alpelisib and paclitaxel, a commonly used agent for GC, were also evaluated. Results: Among eight GC cell lines (SNU1, SNU16, SNU484, SNU601, SNU638, SNU668, AGS, and MKN1), three harbored PIK3CA hotspot mutations: E542K in SNU601, E545A and E453K in AGS, and E545K in MKN1, while the others were PIK3CA wild-type. These three PIK3CA mutant cells were predominantly sensitive to alpelisib. Alpelisib monotherapy decreased AKT and S6K1 phosphorylation and induced G0/G1 cell cycle arrest regardless of PIK3CA mutational status. Moreover, in PIK3CA mutant cells, GSK3β and BAD phosphorylation was potently abrogated by alpelisib alone, which was not evident in PIK3CA wild-type cells. Alpelisib in combination with paclitaxel demonstrated synergistic anti-proliferative effects, preferentially in PIK3CA mutant cells, by increasing caspase 3/7 activity and resulting in increased apoptosis. Moreover, the alpelisib and paclitaxel combination more potently inhibited the cell migration in wound healing assays and the expression of epithelial-mesenchymal transition (EMT)-associated proteins including Snail and Twist in PIK3CA mutant cells, compared with PIK3CA wild-type cells. In a mouse xenograft model of MKN1 cells, alpelisib combined with paclitaxel significantly enhanced the anti-tumor activity by decreasing Ki-67 expression and increasing TUNEL expression. Moreover, this combination tended to prolong survival of tumor-bearing mice for 4 weeks of treatment period without resulting in significant change in body weight. Conclusions: Alpelisib alone or in combination with paclitaxel demonstrated promising anti-tumor activity and tolerability in in vitro and in vivo models of PIK3CA mutant GC via inactivating PI3K down-stream molecules, decreasing cell migration, and increasing apoptosis. Our data suggest that this novel combination is worthy of further clinical investigations in patients with PIK3CA mutant GC. Keywords: alpelisib; BYL719; paclitaxel; PIK3CA; gastric cancer; combination; chemotherapy
Citation Format: Ji-Won Kim, Kui-Jin Kim, Ji Hea Sung, Koung Jin Suh, Ji Yun Lee, Se Hyun Kim, Jin Won Kim, Jeong-Ok Lee, Yu Jung Kim, Soo-Mee Bang, Jee Hyun Kim, Jong Seok Lee, Keun-Wook Lee. Preclinical study of antitumor effect of alpelisib combined with paclitaxel in gastric caner [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C074. doi:10.1158/1535-7163.TARG-19-C074