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Ref Type Journal Article
PMID (38986734)
Authors Zhang H, Zhang L, He Y, Jiang D, Sun J, Luo Q, Liang H, Wang T, Li F, Tang Y, Yang Z, Liu W, Rao Y, Chen C
Title PI3K PROTAC overcomes the lapatinib resistance in PIK3CA-mutant HER2 positive breast cancer.
Journal Vol Issue Date Pages Journal Short Title
Cancer letters 598 2024 Jul 08 217112 Cancer Lett
URL
Abstract Text Although anti-HER2 therapy has made significant strides in reducing metastasis and relapse in HER2-positive breast cancer, resistance to agents like trastuzumab, pertuzumab, and lapatinib frequently develops in patients undergoing treatment. Previous studies suggest that the hyperactivation of the PI3K-AKT signaling pathway by PIK3CA/PTEN gene mutations is implicated in HER2 resistance. In this study, we introduce a novel PI3K-p110α Proteolysis TAargeting Chimera (PROTAC) that effectively inhibits the proliferation of breast cancer cells by degrading PI3K-p110α. When tested in two lapatinib-resistant cell lines, JIMT1 and MDA-MB-453, both of which harbor PIK3CA mutations, the PI3K PROTAC notably reduced cell proliferation and induced G1 phase cell cycle arrest. Importantly, even at very low concentrations, PI3K PROTAC restored sensitivity to lapatinib. Furthermore, the efficacy of PI3K PROTAC surpassed that of Alpelisib, a selective PI3K-p110α kinase inhibitor in clinic. The superior performance of PI3K PROTAC was also confirmed in lapatinib-resistant breast cancer xenograft tumors and patient-derived breast cancer organoids (PDOs). In conclusion, this study reveals that the novel PI3K PROTAC we synthesized could serve as an effective agent to overcome lapatinib resistance.

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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
ZM-PI05 ZM-PI05 3 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
ZM-PI05 ZM PI05|ZMPI05 PI3K Inhibitor (Pan) 42 ZM-PI05 is a proteolysis-targeting chimera (PROTAC) targeting PI3K, which potentially degrades Pik3ca and Pik3r1 and inhibits proliferation and tumor growth (PMID: 38986734).
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 C420R Her2-receptor positive breast cancer sensitive ZM-PI05 Preclinical - Cell line xenograft Actionable In a preclinical study, ZM-PI05 induced cell cycle arrest and decreased viability of an ERBB2 (HER2)-positive breast cancer cell line harboring PIK3CA C420R in culture and inhibited tumor growth in a cell line xenograft model (PMID: 38986734). 38986734
PIK3CA E545K breast cancer sensitive ZM-PI05 Preclinical - Cell culture Actionable In a preclinical study, ZM-PI05 decreased viability of a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 38986734). 38986734
PIK3CA H1047R Her2-receptor positive breast cancer sensitive ZM-PI05 Preclinical - Cell culture Actionable In a preclinical study, ZM-PI05 induced cell cycle arrest and decreased viability of ERBB2 (HER2)-positive breast cancer cell lines harboring PIK3CA H1047R in culture (PMID: 38986734). 38986734