Association of PARP inhibitors and docetaxel resistance through suppressing a tumor microenvironment-associated secretory program.

Abstract

e22212 Background: Acquired resistance to therapeutics accounts for the majority of treatment failures in metastatic cancer. In response to genotoxic stress induced by therapeutics such as radiation and chemotherapy, tumor microenvironment (TME) undergoes marked molecular alterations manifested by increased secretion of cytokines and growth factors, which in turn promote tumor growth, facilitate epithelial-mesenchymal transition, and ultimately result in resistance to chemotherapy. Fibroblasts are a major component of TME and a primary source of cytokines and growth factor secretion following damage. Preliminary results from our lab indicated PARP1 may be involved in regulating this secretory program. We hypothesized that PARP inhibition would suppress the TME-associated secretory program and thereby overcome chemotherapy resistance. Methods: Transcript profiles of cytokines and growth factors were analyzed with quantitative real-time PCR and cDNA microarrays in prostate fibroblasts after treatment with radiation or docetaxel, in combination with one of three PARP inhibitors (PARPi). We evaluated the effects of the docetaxel-induced fibroblast secretory program, in the absence or presence of PARPi, on the proliferation and drug sensitivity of prostate cancer cell lines. Results: Similar to radiation, docetaxel induced the secretion of cytokines and growth factors in prostate fibroblasts. PARP1 was activated by docetaxel treatment. Exposure to PARPi suppressed the docetaxel-induced secretory program. Further analysis suggested that PARPi abrogates activation of p38MAPK pathway. While conditioned medium from docetaxel-treated prostate fibroblasts stimulated growth and chemotherapy resistance, the addition of PARPi attenuated these effects. Conclusions: Docetaxel induces extracellular secretion of pro-tumorigenic cytokines and growth factors by components of the TME. PARP inhibitors attenuated docetaxel resistance through suppression of this secretory program, supporting a new mechanism of action for this class of drugs. Combinatorial use of cytotoxic agents and microenvironment-directed therapies may reduce treatment resistance.