Predictive and Pharmacodynamic Biomarkers of Response to the Phosphatidylinositol 3-Kinase Inhibitor Taselisib in Breast Cancer Preclinical Models.

Abstract

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.

• Authors: Heather M Moore, Heidi M Savage, Carol O'Brien, Wei Zhou, Ethan S Sokol, Michael E Goldberg, Ciara Metcalfe, Lori S Friedman, Mark R Lackner, Timothy R Wilson
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 19 Issue 1 Pg. 292-303 (01 2020) ISSN: 1538-8514 [Electronic] United States
• PMID: 31534012 (Publication Type: Journal Article)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• 2-(3-(2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
• Antineoplastic Agents
• Biomarkers
• Imidazoles
• Oxazepines

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Biomarkers (metabolism)
• Breast Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Female
• Humans
• Imidazoles (pharmacology, therapeutic use)
• Oxazepines (pharmacology, therapeutic use)