Abstract SY19-01: Therapeutic network re-wiring of the DNA damage response can be used to enhance tumor killing by cytotoxic chemotherapy

Abstract

Dynamic re-wiring of signaling networks is a prominent mechanism responsible for the development of resistance to many molecular-targeted anti-cancer agents. Here we show how this same dynamic re-wiring process can be used therapeutically to enhance the response of tumors to cytotoxic anti-cancer agents. Using cell lines and murine tumor models of triple-negative breast cancer, non-small cell lung cancer, and head and neck cancer, we show that chronic inhibition of EGFR and/or FGFR driver oncogenes dramatically enhances cell death in response to topoisomerase inhibitors and platinum DNA crosslinking drugs. In marked contrast, no such sensitization is observed when the growth factor receptor inhibitors are co-administered with the cytotoxic agents. The molecular mechanism responsible for this time-dependent growth factor inhibitor-induced tumor cell sensitization was explored using a systems biology-based model of DNA damage signaling in which protein kinase activities, substrate phosphorylation, and phosphoprotein-binding events for multiple signaling pathways were quantitatively measured at densely sampled points in time, and mathematically correlated with tumor cell responses including cell cycle arrest, cytokine production, autophagy, and apoptosis. This analysis revealed that sustained EGFR/FGFR suppression unmasks an apoptotic network involving Caspase-8 that is normally suppressed by oncogene addiction, resulting in an enhanced apoptotic response to equivalent amounts of DNA damage. This discovery demonstrates that the timing interval between administration of different drugs in combination chemotherapy can have profound effects on the tumor response through the dynamic re-wiring of cell signaling pathways in real time. Finally, we take advantage of this dynamic re-wiring process by developing tumor-targeted time-staggered release nanoparticles that deliver EGFR inhibitors at early times followed by the delayed release of doxorubicin. We show that these nanoparticles cause dramatic regression of murine NSCLC and TNBC tumor xenografts in vivo, substantiating the utility of therapeutic network re-wiring for anti-cancer therapy in the clinic. Citation Format: Michael J. Lee, Yogesh Dayma, Anne-Margriet Heijinks, Stephen W. Morton, Erik C. Dreaden, Paula T. Hammond, Michael B. Yaffe. Therapeutic network re-wiring of the DNA damage response can be used to enhance tumor killing by cytotoxic chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY19-01. doi:10.1158/1538-7445.AM2015-SY19-01