Abstract BBO-10203 is a first-in-class clinical stage small molecule that disrupts the interaction between RAS and PI3Kα resulting in blockade of RAS-driven PI3Kα pathway activation. Unlike PI3Kα kinase inhibitors, BBO-10203 inhibits PI3Kα signaling without directly targeting the kinase domain, thereby preventing hyperglycemia, as insulin receptor signaling does not rely on RAS proteins. BBO-10203 suppresses PI3Kα activation in preclinical models harboring oncogenic KRAS and/or PIK3CA mutations and exhibits complete suppression of AKT phosphorylation (pAKT) in most HER2 amplified or overexpressing cell lines (HER2+). Importantly, this potent inhibitory effect on pAKT drives robust efficacy in HER2+ xenograft models in vivo. Although much is known about HER2 and RAS signaling in tumor cells, it is not clear how inhibiting the interaction of RAS and PI3Kα results in pAKT inhibition in HER2+ cells. Using the HER2+ KYSE-410 esophageal cancer cell line we demonstrate that BBO-10203 inhibits PI3Kα /AKT signaling in HER2+ cells via a mechanism that is mainly driven through non-canonical RAS proteins. CRISPR-mediated knock-in of the PIK3CA RAS-binding domain (RBD) mutations (T208D/K227A), which disrupt the interaction of RAS with PI3Kα, significantly reduced pAKT in the KYSE-410 model, strongly supporting the role of RAS proteins in driving pAKT signaling. Treatment with the panRAS inhibitor RMC-6236 showed little effect on pAKT, suggesting that canonical RAS (K-, H- and N-RAS) may not be important players in pAKT signaling. Among individual RAS isoforms screened via siRNA knockdown, only RRAS/RRAS2 knockdown significantly reduced pAKT, whereas knockdown of other RAS members either elevated pAKT (consistent with compensatory expression) or had no effect. Through co-immunoprecipitation experiments, we identified that RRAS2 is present in the same protein complex as HER2 and HER3, providing mechanistic evidence that this association may contribute to pAKT activation in HER2+ cells. Current efforts are focused on elucidating how BBO-10203 affects the interaction of HER2/3, p85/110α and RRAS2 in HER2+ and other RTK-overexpressing cell line models. Given its orthogonal method of pAKT inhibition and potent activity in HER2+ models, we hypothesized that BBO-10203 would show combination activity with standard-of-care HER2-targeted therapies in HER2+ xenograft models. Indeed, BBO-10203 enhanced the anti-tumor activity of HER2-targeted therapies (tucatinib, trastuzumab, or Enhertu) in vivo, leading to tumor regression, even in the trastuzumab-resistant JIMT-1 model. BBO-10203 has entered phase 1 clinical trials (NCT06625775) and is being evaluated in HER2+ breast cancers, both as a monotherapy and in combination with trastuzumab. Citation Format: Siyu Feng, Cindy Feng, Miranda Cabanski-Dunning, Cathy Zhang, Ming Chen, Erin Riegler, Daniel J. Czyzyk, Yue Yang, Rui Xu, Eli M. Wallace, Dhirendra K. Simanshu, Dwight V. Nissley, Frank McCormick, Kerstin W. Sinkevicius, James P. Stice, Pedro J. Beltran. The RAS: PI3Kα breaker BBO-10203 inhibits PI3Kα/AKT activity in HER2+ models through non-canonical RAS signaling blockade abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6780.
Feng et al. (Fri,) studied this question.