Abstract 4031: Novel tumor intrinsic vs. extrinsic mechanisms of resistance to chemotherapy in metastatic disease

For patients with metastatic triple-negative breast cancer (TNBC), where metastasis occurs in 30% of patients, treatment options are limited to chemotherapy, given the lack of any effective targeted therapies approved for this subtype. However, the response rate is low and the time to relapse is short. While most chemotherapeutic drugs target proliferating cells, we set out to investigate the effect of these drugs on metastatic cells and identify metastasis-specific mechanisms of resistance. In preliminary experiments, mice with triple-negative xenograft tumors and known metastatic disease were treated with taxol and doxorubicin, two drugs commonly used to treat metastatic TNBC patients. Both drugs significantly slowed tumor growth; however, taxol, but not doxorubicin, treatment reduced cell motility within the primary tumor as measured by intravital imaging. These data support the idea that chemotherapeutics can have different effects on growth and motility in vivo, and that effects on tumor size might not correlate with changes in cell motility. We first focused on identifying tumor-intrinsic mechanisms of resistance to chemotherapy. We found that cells expressing the proinvasive isoform of the actin regulatory protein Mena are resistant to the taxane paclitaxel, but not to the widely used DNA-damaging agents doxorubicin or cisplatin. Furthermore, paclitaxel treatment does not attenuate growth of MenaINV-driven metastatic lesions or reduce metastatic burden. Mechanistically, Mena isoform expression alters the ratio of dynamic and stable microtubule populations in paclitaxel-treated cells, while also increasing MAPK signaling in response to paclitaxel treatment. Our data indicate that highly metastatic cells may respond differently to chemotherapeutic drugs than nonmetastatic ones. Second, we investigated the role of tumor extrinsic factors on chemoresistance of metastatic cells, focusing on the extracellular matrix, which is known to drive local invasion and metastasis. We found that in vitro, plating TNBC cells on collagen renders cells more resistant to doxorubicin, but not taxol. In vivo, both taxol and doxorubicin treatments led to increases in collagen deposition. Our data suggest that chemotherapeutic treatments can therefore lead to changes in tumor ECM amount and can also change how cells respond to tumor ECM. Further studies are under way to identify the role of the matrix in chemoresistance. Together, these data indicate that chemotherapeutic drugs, commonly used to treat metastatic disease, have different effects on cell growth vs. cell migration, and that chemotherapy can lead to the generation of prometastatic environments. Citation Format: Madeleine J. Oudin, Lucie Barbier, Tatiana Kosciuk, Emanuel Kreidl, Frank Gertler. Novel tumor intrinsic vs. extrinsic mechanisms of resistance to chemotherapy in metastatic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4031.