Reference Detail

Ref Type

Journal Article

PMID

(30003928)

Authors

Liu XL, Xu YC, Wang YX, Chen Y, Wang BB, Wang Y, Chen YH, Tan C, Hu LD, Ma QY, Zhang YC, Sun YM, Gao YL, Yang CH, Ding J, Meng LH

Title

Decrease in phosphorylated ERK indicates the therapeutic efficacy of a clinical PI3Kα-selective inhibitor CYH33 in breast cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer letters	433		2018 10 01	273-282	Cancer Lett

URL

Abstract Text

PI3Ks are frequently hyper-activated in breast cancer and targeting PI3Kα has exhibited promising but variable response in preclinical and clinical settings. CYH33 is a novel PI3Kα-selective inhibitor in phase I clinical trial. We investigated the efficacy of CYH33 against breast cancer and explored potential predictive biomarkers. CYH33 potently restrained tumor growth in mice bearing human breast cancer cell xenografts and in R26-Pik3caH1047R;MMTV-Cre transgenic mice. CYH33 significantly inhibited proliferation of a panel of human breast cancer cells, while diversity in sensitivity has been observed. Cells harboring activating PIK3CA mutation, amplified HER2 were more responsive to CYH33 than their counterparts. Besides, cells in HER2-enriched or luminal subtype were more sensitive to CYH33 than basal-like breast cancer. Sensitivity to CYH33 has been further revealed to be associated with induction of G1 phase arrest and simultaneous inhibition of Akt and ERK. Sensitivity of patient-derived xenograft to CYH33 was also positively correlated with decrease in phosphorylated ERK. Taken together, CYH33 is a promising PI3Kα inhibitor for breast cancer treatment and decrease in ERK phosphorylation may indicate its efficacy, which provides useful clues for rational design of the ongoing clinical trials.

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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
CYH33	CYH33	7	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CYH33		CYH-33\|CYH 33\|HH-CYH33\|HHCYH 33	PIK3CA inhibitor 23	CCYH33 is a PIK3CA inhibitor that suppresses the activation of Pi3k/Akt/Mtor signaling, which potentially induces cell cycle arrest and inhibits tumor growth (PMID: 30003928).

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 P539R	breast cancer	predicted - sensitive	CYH33	Preclinical - Cell culture	Actionable	In a preclinical study, CYH33 inhibited proliferation of a breast cancer cell line harboring PIK3CA P539R in culture (PMID: 30003928).	30003928
PIK3CA E545K	breast cancer	predicted - sensitive	CYH33	Preclinical - Cell culture	Actionable	In a preclinical study, CYH33 inhibited proliferation of a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 30003928).	30003928
PIK3CA E542K PTEN loss	breast cancer	predicted - sensitive	CYH33	Preclinical - Cell culture	Actionable	In a preclinical study, CYH33 inhibited proliferation of a breast cancer cell line harboring PIK3CA E542K and PTEN loss in culture (PMID: 30003928).	30003928
PTEN loss	breast cancer	no benefit	CYH33	Preclinical - Cell culture	Actionable	In a preclinical study, PTEN loss was not associated with sensitivity to CYH33 in breast cancer cell lines in culture (PMID: 30003928).	30003928
PIK3CA H1047R	breast cancer	sensitive	CYH33	Preclinical - Cell line xenograft	Actionable	In a preclinical study, CYH33 inhibited proliferation of breast cancer cell lines harboring PIK3CA H1047R in culture, inhibited tumor progression in a transgenic mouse model, and induced cell cycle arrest, and inhibited PI3K signaling and tumor growth in cell line xenograft models (PMID: 30003928).	30003928
PIK3CA H1047R PTEN loss	breast cancer	predicted - sensitive	CYH33	Preclinical - Cell culture	Actionable	In a preclinical study, CYH33 inhibited proliferation of a breast cancer cell line harboring PIK3CA H1047R and PTEN loss in culture (PMID: 30003928).	30003928
PIK3CA mutant	breast cancer	predicted - sensitive	CYH33	Preclinical - Cell culture	Actionable	In a preclinical study, breast cancer cell lines harboring PIK3CA mutations demonstrated increased sensitivity to CYH33 compared to cell lines with wild-type PIK3CA in culture (p<0.01) (PMID: 30003928).	30003928