HSP90 inhibitor AUY922 abrogates up‐regulation of RTKs by mTOR inhibitor AZD8055 and potentiates its antiproliferative activity in human breast cancer

摘要: mTOR inhibition led to activation of upstream receptor tyrosine kinases (RTKs) and AKT, which may attenuate the efficacy kinase inhibitors. We sought discover efficient drug combination with inhibitors by elucidating survival feedback loops induced in breast cancer. The signaling upon treatment inhibitor AZD8055 was determined combinatorial activity HSP90 AUY922 cell proliferation were detected. Treatment cancer T47D cells AKT phosphatidylinositol 3-kinase (PI3K), accompanied increase expression multiple proteins including EGFR, HER2, HER3 IRS-1. Different RTKs revealed be responsible for reactivation different lines. Down-regulation these differentially enhanced antiproliferative AZD8055. displayed synergistic effect against a panel human irrespective their genotype, associated cycle arrest DNA synthesis. destabilized tested abrogated also inhibited up-regulation HSP70 HSP27 treatment. Cotreatment two drugs demonstrated triple negative MDA-MB-468 xenograft without toxicity. various types established mechanistic rationale approach using catalytic