Abstract 608: NEOS-223 is a small molecule kinase inhibitor which induces apoptosis in selected cancer models

Abstract

Abstract Due to their critical role in cancer signaling pathways, members of the kinase family have emerged as one of the most comprehensively pursued targets in pharmacological cancer research. Deregulation of kinase activities leads to a variety of upstream and downstream signaling pathway changes in cancer cell. The Ras/Raf/MEK/ERK and PI3K/Akt/mTOR cascades are activated by genetic alterations in selected upstream signaling molecules such as receptor tyrosine kinases. Recently developed therapies which target such kinases (EGFR, BRAF, MEK) with kinase inhibitors have notably improved the prognosis within various cancer patient groups. However, patients with different mutations of EGFR, RAS, and BRAF do not respond completely. In this study the potential of NEOS-223 as a new kinase-targeted therapy in selected cancer models was investigated. Multiple cancer cell lines were assessed for cell growth as well as the direct inhibitory effects of NEOS-223 alone and in combination with other clinically approved kinase inhibitors. NEOS-223 treatment caused cell growth inhibition, blocked colony growth, and induced apoptosis in lung, pancreatic, melanoma, and colon cancer cell lines in vitro and demonstrated potent antitumor activity in in vivo xenograft models of colon and lung cancer. We were particularly interested in examining different components of the ERK and PI3K signaling pathways in selected sensitive cell lines, it was identified that NEOS-223 treatment led to downregulation of the expression of pERK and pAKT signaling. Blockage of the PI3K/mTOR pathways showed inhibitory synergy with NEOS-223 in lung cancer in vitro. Most importantly, in vivo data showed that while administration of NEOS-223 alone decreased tumor growth, the addition of PI3K/Akt/mTOR inhibitor onatasertib significantly enhanced anticancer effect in a lung cancer model. In lung and pancreatic cancer models, inhibition of EGFR by the small molecule drug gefitinib strongly showed synergistic effect with NEOS-223 both in vitro and in vivo. This may be because EGFR potentially activates both the mitogen activated protein kinase (MAPK/ERK) and the PI3K/mTOR signaling cascades in different mutant cancer models. These studies reveal that NEOS-223 inhibits cell proliferation and induces apoptosis via suppressing the PI3K/Akt/mTOR pathway and further suggest that the combination of PI3K/Akt/mTOR and EGFR inhibitors and that NEOS-223 would be a strong potential chemotherapeutic strategy against lung and pancreatic cancers. Citation Format: Harish Potu, Sara A. Little, Stephanie Fedorchak, Sumathi Chittamuru, Timothy M Murphy, Roseanne Wexler, Sarah Di Croce, Melanie George, Laxman S. Desai. NEOS-223 is a small molecule kinase inhibitor which induces apoptosis in selected cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 608.