Cell Line-Specific Network Models of ER⁺ Breast Cancer Identify Potential PI3Kα Inhibitor Resistance Mechanisms and Drug Combinations.

ABSTRACT: Durable control of invasive solid tumors necessitates identifying therapeutic resistance mechanisms and effective drug combinations. In this work, we used a network-based mathematical model to identify sensitivity regulators and drug combinations for the PI3Kα inhibitor alpelisib in estrogen receptor positive (ER⁺) PIK3CA-mutant breast cancer. The model-predicted efficacious combination of alpelisib and BH3 mimetics, for example, MCL1 inhibitors, was experimentally validated in ER⁺ breast cancer cell lines. Consistent with the model, FOXO3 downregulation reduced sensitivity to alpelisib, revealing a novel potential resistance mechanism. Cell line-specific sensitivity to combinations of alpelisib and BH3 mimetics depended on which BCL2 family members were highly

SUBMITTER: Gomez Tejeda Zanudo J 

PROVIDER: S-EPMC8744502 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature