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Ref Type Journal Article
PMID (31534012)
Authors Moore HM, Savage HM, O'Brien C, Zhou W, Sokol ES, Goldberg ME, Metcalfe C, Friedman LS, Lackner MR, Wilson TR
Title Predictive and Pharmacodynamic Biomarkers of Response to the Phosphatidylinositol 3-Kinase Inhibitor Taselisib in Breast Cancer Preclinical Models.
Journal Molecular cancer therapeutics
Vol 19
Issue 1
Date 2020 01
URL
Abstract Text The PI3K signaling pathway serves as a central node in regulating cell survival, proliferation, and metabolism. PIK3CA, the gene encoding the PI3K catalytic subunit p110-alpha, is commonly altered in breast cancer resulting in the constitutive activation of the PI3K pathway. Using an unbiased cell line screening approach, we tested the sensitivity of breast cancer cell lines to taselisib, a potent PI3K inhibitor, and correlated sensitivity with key biomarkers (PIK3CA, HER2, PTEN, and ESR1). We further assessed how taselisib modulates downstream signaling in the different genomic backgrounds that occur within breast cancer. We found that sensitivity to taselisib correlated with the presence of PIK3CA mutations, but was independent of HER2 status. We further showed that HER2-amplified/PIK3CA wild-type cell lines are not as sensitive to taselisib when compared with HER2-amplified/PIK3CA-mutant cell lines. In a PIK3CA-mutant/PTEN null background, PI3K downstream signaling rebounded in the presence of taselisib correlating with decreased sensitivity at later time points. Finally, we observed that PIK3CA mutations cooccurred with mutations in the estrogen receptor (ER; ESR1) in metastatic tumors from patients with ER+ breast cancer. However, the cooccurrence of an ESR1 mutation with a PIK3CA mutation did not affect response to taselisib in a single agent setting or in combination with fulvestrant. In summary, these data suggest that development of taselisib in breast cancer should occur in a PIK3CA-mutant setting with cotreatments determined by the specific subtypes under investigation.

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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
PIK3CA E542K PTEN loss breast cancer sensitive Taselisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA E542K was sensitive to treatment with Taselisib (GDC-0032) in culture, demonstrating decreased cell viability (PMID: 31534012). 31534012
PIK3CA H1047R PTEN loss breast cancer sensitive Taselisib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring a PIK3CA H1047R and PTEN loss was sensitive to treatment with Taselisib (GDC-0032) in culture, demonstrating decreased cell viability (PMID: 31534012). 31534012