Abstract 6917: Ba/F3 AKT engineering cell lines, a useful platform for novel drug discovery

Abstract

Abstract AKT, also known as phosphoinositide 3-kinase (PI3K), plays a key role in various signaling cascades involved in cell growth and division, apoptosis inhibition, and angiogenesis. For AKT, which is at the central node of the PI3K/AKT/mTOR signaling pathway, the loss of PTEN, mutation, or amplification of AKT/PIK3CA can lead to the overactivation of the AKT signaling pathway, resulting in the occurrence and development of tumors. Recent studies have also found that AKT activation is associated with drug resistance in tumor therapy. Therefore, AKT has become a hot target for tumor therapy. The AKT family consists of three highly homologous isoforms, AKT1 (PKBα), AKT2 (PKBβ), and AKT3 (PKBγ), with more than 85% homology in their kinase regions. E17K is the most common and well-characterized activating mutation, accounting for approximately 15% of all AKT mutations. Rare mutations mainly include L52R, Q79K, and D323H. The failures of AKT inhibitors LY2780301 and Bayer's BAY1125976 demonstrate the significant challenges and complexities in developing inhibitors of the AKT pathway. Currently, the most advanced AKT inhibitor globally is AstraZeneca's capivasertib, which is primarily indicated for HR+ breast cancer and triple-negative breast cancer. Our group has generated 21 Ba/F3-AKT engineering cell lines, as useful models for novel drug discovery in vitro and in vivo, almost all clinically significant mutations were included, such as common mutations AKT1/2-E17K as well as rare mutations L52R, Q79K, D323H, and others. The Ba/F3-AKT engineering cell lines can be useful for developing and evaluating next-generation AKT inhibitors and exploring newly acquired resistance mutations in AKT. Citation Format: Guoqian Wang, Yao Tang, Jingxiao Xu, Yao Peng, Yu Wang, Jingying Ning, Feng Hao. Ba/F3 AKT engineering cell lines, a useful platform for novel drug discovery [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 6917.