Abstract C082: BBO-10203, a first-in-class, orally bioavailable, selective breaker of the RAS:PI3Kα interaction inhibits tumor growth alone and in combination with KRAS inhibitors in KRAS mutant 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. While PI3Ka kinase inhibitors have been developed, a significant unmet medical 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 novel strategy is to block RAS-mediated activation of PI3Kα, a signaling event prevalent mostly in malignant cells. Here, we report on BBO-10203, a 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 pAKT across a diverse panel of human cancer cell lines with mutations in KRAS or PI3Kα, demonstrating BBO-10203 is agnostic to the mutational status of RAS and PI3Kα and is active in settings where these proteins are wild-type or mutant. BBO-10203 displays excellent drug-like properties and oral bioavailability, and single dose treatment strongly reduces tumor pAKT levels in a dose- and time-dependent manner in the KYSE-410 CDX model, which harbors KRASG12C and HER2amp alterations. Importantly, BBO-10203 does not induce hyperglycemia or hyperinsulinemia during an oral glucose tolerance test in fasted male C57BL/6 mice. In a panel of CDX and PDX models with KRAS mutations, BBO-10203 treatment results in an average tumor growth inhibition exceeding 70%. Since sustained activation of PI3Kα signaling may mediate resistance to KRAS inhibitors, the combination of a KRAS inhibitor with a PI3Kα pathway inhibitor may maximize the response rate and reduce the development of adaptive resistance mechanisms due to full inhibition of both MAPK and PI3Kα signaling. In vitro cellular studies and in vivo CDX, PDX, and GEM model studies show that BBO-10203 significantly enhances the anti-tumor activity of the dual GTP-bound (ON) and GDP-bound (OFF) KRASG12C and pan-KRAS inhibitors BBO-8520 (NCT06343402) and BBO-11818 (NCT06917079), respectively. These combinations induce deep tumor regressions through direct effects on tumor cell proliferation and apoptosis and are well tolerated. In conclusion, BBO-10203 blocks RAS-mediated activation of PI3Kα and strongly inhibits pAKT signaling in tumor cells without affecting glucose metabolism. BBO-10203 has entered phase 1 clinical trials (NCT06625775) and is being evaluated in KRAS mutant CRC and NSCLC, both as a monotherapy and in combination with KRAS inhibitors. Citation Format: Kerstin W. Sinkevicius, James P. Stice, Rui Xu, Cathy Zhang, Siyu Feng, Erin Riegler, Carlos Stahlhut, Kanchan Singh, Daniel J. Czyzyk, John-Paul Denson, Yue Yang, Sofia Donovan, Ming Chen, Cindy Feng, Kyle Sullivan, Nadege Gitego, Michela Ranieri, Magdalena Ploszaj, Katie Parker, Samar Ghorbanpoorvalukolaie, Marcin Dyba, Brian P. Smith, Lijuan Fu, Ken Lin, Felice C. Lightstone, Anna E. Maciag, Keshi Wang, Aaron Hata, Kwok-Kin Wong, Dwight V. Nissley, Eli Wallace, Dhirendra K. Simanshu, Frank McCormick, Pedro J. Beltran. BBO-10203, a first-in-class, orally bioavailable, selective breaker of the RAS:PI3Kα interaction inhibits tumor growth alone and in combination with KRAS inhibitors in KRAS mutant models without inducing hyperglycemia [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C082.

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