Abstract LB-234: A persistently activated signaling network regulates the DNA damage secretory program to promote cancer resistance driven by the therapeutically damaged tumor microenvironment

Abstract

Abstract In cancer clinics, an in vivo form of the senescence-associated secretory phenotype (SASP) is driven by a DNA damage secretory program (DDSP) provoked by side effects of genotoxic therapeutics including chemotherapy and radiation which fuel advanced pathologies particularly cancer resistance. However, the complete mechanism underlying DDSP development in the tumor microenvironment (TME) remains unclear. Here we report that genotoxic agents frequently used in clinical oncology induce a gene expression pattern distinct from the one that is shaped by non-genotoxic drugs. Specifically, the zinc finger and scan domain containing 4 (Zscan4) is upregulated upon DNA damage in stromal cells and engaged in DNA damage response (DDR) in genotoxic settings. Apart from the established functions in telomere elongation and genomic integrity of stem cells, Zscan4 is central for the Rap1/TRF2 assembly and orchestrates the long term DDR signaling in differentiated stromal cells. In response to DNA damage, the mammalian target of rapamycin (mTOR) is phosphorylated in the cytoplasm of stromal cells and relays DDR signals, a phenomenon different from human cancer cells. There are physical interactions between the mTOR and the IKK complexes, events functionally implicating the NF-κB machinery that is regulated by both the IL-1α/IRAK1 and mTOR/Raptor axes. We determined that mTORC1 is a critical mediator of DDSP programmatic implementation by conducting signals from upstream molecules including p38 and PI3K/Akt, molecules activated in DNA damage events. We revealed that the ligand IL-1α signals through IL-1R and TAK1, the latter a member of the mitogen-activated kinase kinase kinase (MAPKKK) family that induces a proinflammatory cascade by activating JNK/p38 and NF-κB. Further, targeting p38, mTOR or TAK1 with small molecule inhibitors in vivo significantly abrogated cancer resistance acquired from the TME in chemotherapeutic cycles. Overall, our study substantiates p38, mTOR and TAK1 as a group of new candidates for future TME-oriented intervention to minimize resistance provoked by anticancer regimes, and suggests that anti-p38/mTOR/TAK1 agents may be repurposed to sensitize tumors by effectively targeting the TME. Our data disclose a novel mechanism of SASP (or DDSP) signaling in classical therapeutic settings, thus opening new avenues to improve clinical outcomes in the current era of precision medicine. Citation Format: Yu Sun, Boyi Zhang, Fei Chen, Paul Chiao. A persistently activated signaling network regulates the DNA damage secretory program to promote cancer resistance driven by the therapeutically damaged tumor microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-234.