Dual inhibition of GTP-bound (ON) and GDP-bound (OFF) KRAS <sup>G12C</sup> suppresses PI3Kα and leads to potent tumor inhibition

. Disruption of the interaction between RAS and PI3Kα using a novel protein:protein interaction inhibitor suppressed PI3Kα-AKT activation and increased the tumor response to sotorasib to a similar level as BBO-8520. Moreover, in some contexts, disruption of RAS-PI3Kα further increased the anti-tumor activity of BBO-8520 monotherapy. These results reveal mechanistic differences between KRAS (ON) and (OFF) inhibitors, highlight the importance of PI3Kα-AKT signaling in driving resistance to KRAS inhibition in lung cancer, and suggest combination strategies that suppress PI3Kα-AKT to improve the response to KRAS inhibitors.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-04-30
DOI
https://doi.org/10.64898/2026.04.27.718135
Primary Topic
Protein Kinase Regulation and GTPase Signaling
Type
article
Field-Weighted Citation Impact
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article

Dual inhibition of GTP-bound (ON) and GDP-bound (OFF) KRAS G12C suppresses PI3Kα and leads to potent tumor inhibition

Sarah Clark, Kwok‐Kin Wong, James P. Stice, Michela Ranieri et al.
bioRxiv (Cold Spring Harbor Laboratory)
Protein Kinase Regulation and GTPase Signaling
article

Dual inhibition of GTP-bound (ON) and GDP-bound (OFF) KRAS G12C suppresses PI3Kα and leads to potent tumor inhibition

Sarah Clark, Kwok‐Kin Wong, James P. Stice, Michela Ranieri, Soumyadip Sahu, Emily Hensley, Hsin‐Yi Huang, Kerstin W. Sinkevicius, Cathy Zhang, Samar Ghorbanpoor, Aaron N. Hata, Wafa Malik, Saman Setoodeh, K. A. Parker, Yi-Xiang Wang, Grace Kelley, Daniel Andrussier, Magdalena Ploszaj, Anna E Maciag, Ken Lin, Lauren Highfield, Frank McCormick, Bin Wang, Pedro J Beltran, Rui Xu, Ting Chen
article en

Abstract

. Disruption of the interaction between RAS and PI3Kα using a novel protein:protein interaction inhibitor suppressed PI3Kα-AKT activation and increased the tumor response to sotorasib to a similar level as BBO-8520. Moreover, in some contexts, disruption of RAS-PI3Kα further increased the anti-tumor activity of BBO-8520 monotherapy. These results reveal mechanistic differences between KRAS (ON) and (OFF) inhibitors, highlight the importance of PI3Kα-AKT signaling in driving resistance to KRAS inhibition in lung cancer, and suggest combination strategies that suppress PI3Kα-AKT to improve the response to KRAS inhibitors.

bioRxiv (Cold Spring Harbor Laboratory)
Leidos (United States) (US), NYU Langone Health (US), Massachusetts General Hospital (US), Frederick National Laboratory for Cancer Research (US), Global Cancer Institute (US), UCSF Helen Diller Family Comprehensive Cancer Center (US), Leidos Biomedical Research Inc. (United States), Cabot (United States) (US)
Decent work and economic growth
Openalex Percentile: Top 11%
Protein Kinase Regulation and GTPase Signaling
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