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Ref Type Journal Article
PMID (21558396)
Authors Tanaka H, Yoshida M, Tanimura H, Fujii T, Sakata K, Tachibana Y, Ohwada J, Ebiike H, Kuramoto S, Morita K, Yoshimura Y, Yamazaki T, Ishii N, Kondoh O, Aoki Y
Title The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations.
URL
Abstract Text The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer. PIK3CA mutations, which are found in many cancer patients, activate the PI3K pathway, resulting in cancer development and progression. We previously identified CH5132799 as a novel PI3K inhibitor. Thus, this study aimed to clarify the biochemical and antitumor activity of CH5132799 and elucidate the correlation between CH5132799 response and genetic alterations in the PI3K pathway.Kinase inhibitory activity was profiled in cell-free assays. A large panel of human breast, ovarian, prostate, and endometrial cancer cell lines, as well as xenograft models, were used to evaluate the antitumor activity of CH5132799, followed by analysis for genetic alterations. Effects on Akt phosphorylation induced by mTORC1 inhibition were tested with CH5132799 and compared with mTORC1 and PI3K/mTOR inhibitors.CH5132799 selectively inhibited class I PI3Ks and PI3Kα mutants in in vitro kinase assays. Tumors harboring PIK3CA mutations were significantly sensitive to CH5132799 in vitro and were remarkably regressed by CH5132799 in in vivo mouse xenograft models. In combination with trastuzumab, tumors disappeared in the trastuzumab-insensitive breast cancer model with the PIK3CA mutation. Moreover, CH5132799 did not reverse a negative feedback loop of PI3K/Akt/mTOR signaling and induced regression against tumors regrown after long-term mTORC1 inhibitor treatment.CH5132799 is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. Prediction of CH5132799 response on the basis of PIK3CA mutations could enable patient stratification in clinical settings.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
MEN1611 MEN1611 21 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
MEN1611 MEN-1611|CH 5132799|CH-5132799|PA 799|PA799|CH5132799|MEN 1611 PI3K Inhibitor (Pan) 40 MEN1611 (CH5132799) inhibits class I PI3Ks, including the PIKC3A mutants E542K, E545K, and H1047R, resulting in decreased PI3K pathway signaling and decreased tumor growth (PMID: 21558396).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA E542K breast cancer sensitive MEN1611 Preclinical Actionable In a preclinical study, MEN1611 (CH5132799) inhibited proliferation of a breast cancer cell line harboring PIK3CA E542K in culture (PMID: 21558396). 21558396
PTEN del prostate cancer sensitive MEN1611 Preclinical - Cell line xenograft Actionable In a preclinical study, MEN1611 (CH5132799) inhibited tumor growth in xenograft models of a human prostate cancer cell line with deletion of PTEN (PMID: 21558396). 21558396
PIK3CA E545K breast cancer sensitive MEN1611 Preclinical Actionable In a preclinical study, MEN1611 (CH5132799) inhibited proliferation of breast cancer cells expressing PIK3CA E545K (PMID: 21558396). 21558396
PIK3CA R38C PTEN loss endometrial cancer sensitive MEN1611 Preclinical Actionable In a preclinical study, MEN1611 (CH5132799) inhibited proliferation of an endometrial cancer cell line harboring PIK3CA R38C and PTEN loss in culture (PMID: 21558396). 21558396
PIK3CA mutant endometrial cancer sensitive MEN1611 Preclinical Actionable In a preclinical study, MEN1611 (CH5132799) inhibited proliferation of endometrial cancer cells with PIK3CA mutations in culture (PMID: 21558396). 21558396
PIK3CA H1047Y endometrial cancer sensitive MEN1611 Preclinical - Cell line xenograft Actionable In a preclinical study, MEN1611 (CH5132799) inhibited cell growth in a human endometrial cancer cell line harboring a PIK3CA H1047Y mutation, and inhibited tumor growth in xenograft models (PMID: 21558396). 21558396
PIK3CA mutant prostate cancer sensitive MEN1611 Preclinical Actionable In a preclinical study, MEN1611 (CH5132799) inhibited proliferation of prostate cancer cells with PIK3CA mutations in culture (PMID: 21558396). 21558396
PIK3CA mutant breast cancer sensitive MEN1611 Preclinical Actionable In a preclinical study, breast cancer cells with PIK3CA mutations, both with and without ERBB2 (HER2) amplification, demonstrated sensitivity to MEN1611 (CH5132799) in culture (PMID: 21558396). 21558396
PIK3CA H1047R breast cancer sensitive MEN1611 Preclinical Actionable In a preclinical study, MEN1611 (CH5132799) inhibited proliferation of breast cancer cells harboring PIK3CA H1047R in culture (PMID: 21558396). 21558396
PIK3CA mutant ovarian cancer sensitive MEN1611 Preclinical Actionable In a preclinical study, MEN1611 (CH5132799) inhibited proliferation of ovarian cancer cells with PIK3CA mutations in culture (PMID: 21558396). 21558396
PTEN del stomach cancer sensitive MEN1611 Preclinical - Cell line xenograft Actionable In a preclinical study, MEN1611 (CH5132799) induced tumor regression in xenograft models of a human stomach cancer cell line with deletion of PTEN (PMID: 21558396). 21558396
PIK3CA E545K ovarian cancer sensitive MEN1611 Preclinical Actionable In a preclinical study, MEN1611 (CH5132799) inhibited proliferation of ovarian cancer cells harboring PIK3CA E545K in culture (PMID: 21558396). 21558396
PIK3CA Q546R prostate cancer sensitive MEN1611 Preclinical Actionable In a preclinical study, MEN1611 (CH5132799) inhibited proliferation of prostate cancer cells harboring PIK3CA Q546R in culture (PMID: 21558396). 21558396