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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 Cancer letters
Vol 433
Issue
Date 2018 10 01
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 10 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CYH33 PIK3CA inhibitor 16 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
ERBB2 amp breast cancer sensitive CYH33 Preclinical - Cell culture Actionable In a preclinical study, breast cancer cell lines harboring ERBB2 (HER2) amplification demonstrated increased sensitivity to CYH33 compared to cells with normal ERBB2 (HER2) expression in culture (p<0.05) (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 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
ERBB2 amp PIK3CA H1047R breast cancer sensitive CYH33 Preclinical - Cell culture Actionable In a preclinical study, CYH33 inhibited proliferation of breast cancer cell lines harboring PIK3CA H1047R and ERBB2 (HER2) amplification in culture (PMID: 30003928). 30003928
ERBB2 amp 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 and ERBB2 (HER2) amplification in culture (PMID: 30003928). 30003928
ERBB2 amp PIK3CA C420R breast cancer sensitive CYH33 Preclinical - Cell culture Actionable In a preclinical study, CYH33 inhibited proliferation of breast cancer cell lines harboring PIK3CA C420R and ERBB2 (HER2) amplification 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
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
Unknown unknown breast cancer not applicable CYH33 Preclinical - Cell culture Actionable In a preclinical study, CYH33 inhibited proliferation of 56% (18/32) of breast cancer cell lines in culture and demonstrated increased activity compared to Piqray (Alpelisib) (PMID: 30003928). 30003928
ERBB2 amp PIK3CA K111N breast cancer predicted - sensitive CYH33 Preclinical - Cell culture Actionable In a preclinical study, CYH33 inhibited proliferation of a breast cancer cell line harboring PIK3CA K111N and ERBB2 (HER2) amplification in culture (PMID: 30003928). 30003928