Abstract PS2-12-06: BBO-10203, a first-in-class breaker of the RAS:PI3Kα interaction, inhibits tumor growth alone and in combination with fulvestrant or ribociclib in breast cancer models without inducing hyperglycemia

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Abstract Aberrant activation of the PI3Kα pathway is one of the most frequent oncogenic events across human cancers and leads to promotion of tumor cell growth, survival, glucose metabolism, and acute resistance to numerous standard of care cancer therapies. Although PI3Kα inhibitors are approved, and mutant-selective PI3Kα inhibitors are in development for treating HR+ HER2- breast cancers with PIK3CA mutations, a significant unmet need remains due to dose-limiting, on-target hyperglycemia. This toxicity can restrict target coverage, limit the number of eligible patients, and shorten the duration of treatment, highlighting the need for novel approaches to target the pathway. One such strategy is to block RAS-mediated activation of PI3Kα, a signaling event prevalent mostly in malignant cells. Here, we report on BBO-10203, a clinical-stage first-in-class small molecule which breaks the protein-protein interaction between RAS and PI3Kα and inhibits RAS-mediated activation of the PI3Kα pathway. Importantly, BBO-10203 does not induce hyperglycemia, as insulin signaling does not rely on RAS proteins to mediate glucose uptake. BBO-10203 covalently and selectively binds PI3Kα on cysteine 242 in the RAS binding domain, which prevents the activation of PI3Kα by KRAS, HRAS, and NRAS. BBO-10203 shows full cellular target engagement at 30 nM and potently inhibits RAS-driven pAKT in human breast cancer cell lines. BBO-10203 displays excellent drug-like properties and oral bioavailability. PK/PD studies show that a single dose significantly reduces tumor pAKT levels in a dose- and time-dependent manner, and efficacy studies show that BBO-10203 has monotherapy activity in a panel of ER+ HER2- breast cancer CDX and PDX models. Importantly, BBO-10203 does not induce hyperglycemia or hyperinsulinemia during an oral glucose tolerance test in fasted male C57BL/6 mice. Since activation of the PI3Kα pathway provides acute resistance to endocrine therapies and CDK4/6 inhibitors in HR+ HER2- breast cancer, BBO-10203 has the potential to enhance the long-term responses in combination with these therapies. In vivo studies show that BBO-10203 significantly enhances the anti-tumor activity of the SERD fulvestrant or the CDK4/6 inhibitor ribociclib in ER+ HER2- CDX and PDX breast cancer models harboring either kinase or helical domain mutations in PIK3CA or wild-type PIK3CA. These combinations induce tumor stasis or regressions through direct effects on tumor cells and are well tolerated. Lastly, we compare the activity of BBO-10203 against next-generation mutant-selective PI3Kα inhibitors. In the EFM-19 CDX model, which harbors a kinase domain PIK3CA mutation, the combination of BBO-10203 and fulvestrant show the same activity as the combination of STX-478 and fulvestrant. In conclusion, BBO-10203 blocks RAS-mediated activation of PI3Kα, strongly inhibits pAKT signaling in tumor cells without affecting glucose metabolism, and shows robust tumor activity alone or in combination with standard of care therapies in mutant or wild-type PIK3CA breast cancer models. BBO-10203 has entered phase 1 clinical trials (NCT06625775) and may provide clinical benefit without the limiting toxicities that have restricted the use of PI3Kα inhibitors. Citation Format: K. W. Sinkevicius, J. P. Stice, C. Zhang, S. Feng, M. Chen, E. Riegler, C. Feng, D. J. Czyzyk, J.-P. Denson, Y. Yang, M. Dyba, B. P. Smith, S. Donovan, L. Fu, K. Lin, F. C. Lightstone, A. E. Maciag, K. Wang, D. V. Nissley, E. M. Wallace, D. K. Simanshu, R. Xu, F. McCormick, P. J. Beltran. BBO-10203, a first-in-class breaker of the RAS:PI3Kα interaction, inhibits tumor growth alone and in combination with fulvestrant or ribociclib in breast cancer models without inducing hyperglycemia [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-12-06.

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