Abstract 2248: Paclitaxel-induced micronucleation activates pro-inflammatory cGAS/STING signaling in triple negative breast cancer

Introduction: Paclitaxel (TaxolTM) is a blockbuster chemotherapy used for solid tumors including breast cancer. In triple-negative breast cancer (TNBC), nab-paclitaxel plus PD-L1 inhibitor, atezolizumab, is now approved based on increased survival compared with nab-paclitaxel alone. We hypothesize that there may be an interaction by which taxane therapy is immunogenic. Paclitaxel induces aberrant cell division on multipolar spindles, which often results in formation of multiple small nuclei. Some of these resemble micronuclei. Here, we test the hypothesis that taxane-induced micronuclei activate cGAS-STING to increase immunogenicity in TNBC. Methods: We evaluate the impact of clinically relevant doses of paclitaxel on TNBC cell lines MDA-MB-231, MDA-MB-453, MDA-MB-468, BT-549 and HCC-1806 on generating micronuclei by immunofluorescence microscopy. Using immunoblotting and qPCR, we evaluate the impact of paclitaxel on cGAS recruitment and activation, STING activation, and interferon-beta production. Furthermore, we co-culture MDA-MB-231 and THP-1 cells to evaluate the impact of paclitaxel on polarization of THP-1 macrophages. We employ CRISPR-mediated cGAS knockout to evaluate its role in mediating these effects. Finally, we test the effect of neoadjuvant paclitaxel (80 mg/m2 qw, 16 treatments/4 cycles) in 4 patients for formation of micronuclei and tumor-infiltrating lymphocytes 20 hours after the third treatment of paclitaxel by HE 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2248.