Abstract 139: M2698, a novel dual inhibitor of p70S6K and Akt: preclinical efficacy in gastric cancer

Abstract

Abstract M2698 is a selective, ATP-competitive dual inhibitor of p70S6K and Akt1/3 that is being evaluated in a phase I clinical trial in cancer patients. The dual nature of M2698 may result in improved clinical efficacy by blocking the increased AKT activity in a compensatory feedback loop induced by PI3K/AKT/mTOR (PAM) pathway inhibition. In previous preclinical studies, M2698 was shown to have potent anti-proliferative activity in vitro, and inhibit tumor growth in some xenograft models in vivo. The current study examined the effects of M2698 on cell proliferation in a panel of 13 gastric cancer cell lines, as gastric cancers often harbor mutations in PAM pathway genes that deregulate this signalling pathway. Cells were treated with M2698 at a range of concentrations and proliferation was evaluated at least twice using the WST-8 cell proliferation assay kit (Dojindo Molecular Technologies, Inc. Japan). Two cell lines, HGC-27 and IM95m, were particularly sensitive to M2698 (50% growth inhibition concentration [GI50] 84 and 160 nM, respectively). The GI50 values for all other cell lines were >10-fold higher. Although HGC-27 and IM95m each carry a PIK3CA hotspot point mutation, the presence of an activating PI3K pathway mutation was not the sole determinant of sensitivity, as a third PIK3CA mutant cell line, MKN1, was far less sensitive to M2698 (GI50 9.0 uM). Western blot analysis of pharmacodynamic biomarkers showed that M2698 (1 uM) blocked the PAM pathway in both sensitive and resistant cell lines, inhibiting phospho[p]-S6 and p-PRAS40, despite increased p-Akt. Some biomarkers from the PAM pathway and other signaling pathways appeared to be associated with sensitivity to M2698, but these candidate biomarkers need to be validated in a larger panel of cell lines. Treatment of HGC-27-tumor-bearing mice with M2698 (10, 20, 30 mg/kg/day) for 14 days resulted in significant tumor growth inhibition (80.2-98.6%) at Day 29 compared to treatment with vehicle (p<0.01). In conclusion, we have shown that gastric cancer cell lines have a range of sensitivities to M2698 and the sensitivity cannot be explained solely by genetic mutations in the PAM pathway. M2698 provides potent PAM pathway inhibition in both sensitive and resistant gastric cancer cell lines by blocking both p70S6K and Akt. M2698 significantly inhibits tumor growth in the HGC-27 xenograft model in vivo. Citation Format: Shota Fukuoka, Takashi Kojima, Yoshikatsu Koga, Mayumi Yamauchi, Masahiro Yasunaga, Yasuhiro Matsumura, Toshihiko Doi, Takayuki Yoshino, Toshio Kuronita, Anderson Clark, Brian Elenbaas, Atsuhi Ohtsu. M2698, a novel dual inhibitor of p70S6K and Akt: preclinical efficacy in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 139. doi:10.1158/1538-7445.AM2017-139