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

Journal Article · · Science
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  1. Frederick National Laboratory for Cancer Research, Frederick, MD (United States)
  2. BridgeBio Oncology Therapeutics, San Francisco, CA (United States)
  3. Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
  4. University of California, San Francisco, CA (United States)
  5. Massachusetts General Hospital, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
  6. BridgeBio Pharma, San Francisco, CA (United States)
  7. Frederick National Laboratory for Cancer Research, Frederick, MD (United States); University of California, San Francisco, CA (United States)
+ Show Author Affiliations
BBO-10203 is an orally available drug that covalently and specifically binds to the rat sarcoma (RAS)–binding domain of phosphoinositide 3-kinase α (PI3Kα), preventing its activation by HRAS, NRAS, and KRAS. Here, it inhibited PI3Kα 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 PI3Kα activation to promote glucose uptake.
Research Organization:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Organization:
National Institutes of HealtH (NIH); USDOE National Nuclear Security Administration (NNSA); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)
Grant/Contract Number:
AC02-06CH11357; AC52-07NA27344
OSTI ID:
2587682
Report Number(s):
LLNL--JRNL-863848
Journal Information:
Science, Journal Name: Science Journal Issue: 6758 Vol. 389; ISSN 1095-9203; ISSN 0036-8075
Publisher:
American Association for the Advancement of Science (AAAS)Copyright Statement
Country of Publication:
United States
Language:
English

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