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Ref Type Journal Article
PMID (36913051)
Authors Fiascarelli A, Merlino G, Capano S, Talucci S, Bisignano D, Bressan A, Bellarosa D, Carrisi C, Paoli A, Bigioni M, Tunici P, Irrissuto C, Salerno M, Arribas J, de Stanchina E, Scaltriti M, Binaschi M
Title Antitumor activity of the PI3K δ-sparing inhibitor MEN1611 in PIK3CA mutated, trastuzumab-resistant HER2 + breast cancer.
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Abstract Text Dysregulation of the PI3K pathway is one of the most common events in breast cancer. Here we investigate the activity of the PI3K inhibitor MEN1611 at both molecular and phenotypic levels by dissecting and comparing its profile and efficacy in HER2 + breast cancer models with other PI3K inhibitors.Models with different genetic backgrounds were used to investigate the pharmacological profile of MEN1611 against other PI3K inhibitors. In vitro studies evaluated cell viability, PI3K signaling, and cell death upon treatment with MEN1611. In vivo efficacy of the compound was investigated in cell line- and patient-derived xenografts models.Consistent with its biochemical selectivity, MEN1611 demonstrated lower cytotoxic activity in a p110δ-driven cellular model when compared to taselisib, and higher cytotoxic activity in the p110β-driven cellular model when compared to alpelisib. Moreover, MEN1611 selectively decreased the p110α protein levels in PIK3CA mutated breast cancer cells in a concentration- and proteasome-dependent manner. In vivo, MEN1611 monotherapy showed significant and durable antitumor activity in several trastuzumab-resistant PIK3CA-mutant HER2 + PDX models. The combination of trastuzumab and MEN1611 significantly improved the efficacy compared to single agent treatment.The profile of MEN1611 and its antitumoral activity suggest an improved profile as compared to pan-inhibitors, which are limited by a less than ideal safety profile, and isoform selective molecules, which may potentially promote development of resistance mechanisms. The compelling antitumor activity in combination with trastuzumab in HER2 + trastuzumab-resistant, PIK3CA mutated breast cancer models is at the basis of the ongoing B-Precise clinical trial (NCT03767335).

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
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
PTEN F90Lfs*90 breast cancer sensitive MEN1611 Preclinical - Cell culture Actionable In a preclinical study, MEN1611 (CH5132799) inhibited viability in a breast cancer cell line harboring PTEN F90Lfs*90 in culture (PMID: 36913051). 36913051
PTEN D92H PTEN F278Lfs*12 breast cancer sensitive MEN1611 Preclinical - Cell culture Actionable In a preclinical study, MEN1611 (CH5132799) inhibited viability in a breast cancer cell line harboring PTEN D92H and F278Lfs*12 in culture (PMID: 36913051). 36913051
PIK3CA P539R PIK3CA H1047R PTEN del breast cancer sensitive MEN1611 Preclinical - Cell culture Actionable In a preclinical study, MEN1611 (CH5132799) inhibited viability in a breast cancer cell line with deletion of PTEN and harboring PIK3CA H1047R and P539R in culture (PMID: 36913051). 36913051
PIK3CA K111N breast cancer sensitive MEN1611 Preclinical - Cell culture Actionable In a preclinical study, MEN1611 (CH5132799) inhibited viability in a breast cancer cell line harboring PIK3CA K111N in culture (PMID: 36913051). 36913051
PTEN L108R breast cancer sensitive MEN1611 Preclinical - Cell culture Actionable In a preclinical study, MEN1611 (CH5132799) inhibited viability in a breast cancer cell line harboring PTEN L108R in culture (PMID: 36913051). 36913051
PTEN del breast cancer sensitive MEN1611 Preclinical - Cell culture Actionable In a preclinical study, MEN1611 (CH5132799) inhibited viability in breast cancer cell lines harboring a PTEN deletion in culture (PMID: 36913051). 36913051
PIK3CA H1047R breast cancer sensitive MEN1611 Preclinical - Cell culture Actionable In a preclinical study, MEN1611 (CH5132799) inhibited viability and induced degradation of p110alpha in breast cancer cell lines harboring PIK3CA H1047R in culture (PMID: 36913051). 36913051