Inhibition Of Rapamycin-Induced Feedback Activation Of Akt With Dasatinib Induces Complete Tumor Regression In A Preclinical Model Of Breast Cancer.
CANCER RESEARCH(2013)
Abstract
Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC
Resistance to receptor tyrosine kinase (RTK) blockade in breast cancer treatment is commonly mediated by activation of bypass pathways that sustain growth. We propose moving away from the individual targeting of RTKs to inhibit multiple commonly activated, overlapping, and essential downstream pathways. The mammalian Target of Rapamycin (mTOR) and the non-receptor tyrosine kinase, Src, are two intrinsic targets that intersect downstream of most RTKs. To date, limited clinical efficacy has been shown with either mTOR or Src inhibitors as single agents. Here we show that dasatinib, a dual Src/c-abl inhibitor, is able to block the well-established de-repression of AKT that occurs with rapamycin inhibition of mTOR. Furthermore, dual inhibition of these distinct, but compensatory arms of RTK signaling results in rapid and complete regression in over 80% of MMTV-PyMT-induced mammary tumors, with only moderate effects on tumor inhibition as single agents. Importantly, Src and mTOR pathway co-activation occurs in nearly half of human breast cancers, independent of tumor sub-type. These studies support the evaluation of combined mTOR and Src inhibitors in breast cancer patients. Such inhibitors are currently FDA approved, expediting the transition to clinical safety and efficacy trials. We expect this approach will prevent molecular evolution of bypass pathways and induce tumor regression.
Citation Format: Jennifer L. Yori, Kristen Lozada, Darcie D. Seachrist, Jonathan Mosley, Fadi W. Abdul-Karim, Christine N. Booth, Chris A. Flask, Ruth A. Keri. Inhibition of rapamycin-induced feedback activation of AKT with dasatinib induces complete tumor regression in a preclinical model of breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-221. doi:10.1158/1538-7445.AM2013-LB-221
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Key words
complete tumor regression,breast cancer,akt,rapamycin-induced
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