Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	17	10	2011 May 15	3272-81	Clin Cancer Res

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) 42	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 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
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	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 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
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	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 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 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 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
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
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
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