BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3Kα interaction

• 成果类型: Article
• 署名作者: Simanshu, Dhirendra K.; Xu, Rui; Stice, James P.; Czyzyk, Daniel J.; Feng, Siyu; Denson, John-Paul; Riegler, Erin; Yang, Yue; Zhang, Cathy; Donovan, Sofia; Smith, Brian P.; Abreu-Blanco, Maria; Chen, Ming; Feng, Cindy; Fu, Lijuan; Rabara, Dana; Young, Lucy C.; Dyba, Marcin; Yan, Wupeng; Lin, Ken; Ghorbanpoorvalukolaie, Samar; Larsen, Erik K.; Malik, Wafa; Champagne, Allison; Parker, Katie; Ju, Jin Hyun; Jeknic, Stevan; Esposito, Dominic; Turner, David M.; Lightstone, Felice C.; Wang, Bin; Wehn, Paul M.; Wang, Keshi; Stephen, Andrew G.; Maciag, Anna E.; Hata, Aaron N.; Sinkevicius, Kerstin W.; Nissley, Dwight V.; Wallace, Eli M.; McCormick, Frank; Beltran, Pedro J.
• 署名单位: National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; United States Department of Energy (DOE); Lawrence Livermore National Laboratory; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12977
• DOI: 10.1126/science.adq2004
• 发表日期: 2025-07-24
• 页码: 409-415
• 关键词: phosphatidylinositol kinase-activity; ras; gene; p110-alpha; pi3k-alpha; expression; mutations; subunit; protein; pi3k

摘要

BBO-10203 is an orally available drug that covalently and specifically binds to the rat sarcoma (RAS)-binding domain of phosphoinositide 3-kinase alpha (PI3K alpha), preventing its activation by HRAS, NRAS, and KRAS. It inhibited PI3K alpha activation in tumors with oncogenic mutations in KRAS or PIK3CA and in tumors with human epidermal growth factor receptor 2 (HER2) amplification or overexpression. In preclinical models, BBO-10203 caused significant tumor growth inhibition across multiple tumor types and showed enhanced efficacy in combination with inhibitors of cyclin-dependent kinase 4/6 (CDK4/6), estrogen receptor (ER), HER2, and KRAS-G12C mutant, including in tumors harboring mutations in Kelch-like ECH-associated protein 1 (KEAP1) and serine/threonine kinase 11 (STK11). Notably, these antitumor effects occurred without inducing hyperglycemia, because insulin signaling does not depend on RAS-mediated PI3K alpha activation to promote glucose uptake.