Abstract
Abstract Lack of durable response to cytotoxic chemotherapy is a major contributor to the dismal outcomes seen in pancreatic ductal adenocarcinoma (PDAC). Extensive tumor desmoplasia and poor vascular supply are two predominant characteristics that hinder the delivery of chemotherapeutic drugs into PDAC tumors and mediate resistance to therapy. Previously, we have shown that STAT3 is a key biomarker of therapeutic resistance to gemcitabine treatment in PDAC, which can be overcome by combined inhibition of the Src kinase and epidermal growth factor receptor (EGFR) pathways. Although it is well established that concurrent EGFR and Src inhibition exert these anti-eoplastic properties through inhibiting mitogenic pathways in tumor cells directly, the influence of this combined therapy on stromal constituents in PDAC tumors remains unknown. In the present study, we demonstrate in both orthotopic tumor xenografts and Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mouse models that concurrent EGFR and Src inhibition abrogates STAT3 activation, resulting in stromal remodeling through the depletion of tumor collagen content, increasing microvessel density, and preventing tissue fibrosis in vivo. Furthermore, these stromal changes resulting from combined pathway inhibition produce a direct increase in intratumoral gemcitabine levels as determined by MALDI-IMS and improve overall survival in PKT mice treated with combined EGFR and Src inhibition with gemcitabine. As a phase 1 clinical trial utilizing concurrent EGFR and Src inhibition in combination with gemcitabine has recently concluded, these data provide translational insight into the novel mechanism of action of this regimen and expand our understanding into the phenomenon of stromal-mediated therapeutic resistance. Citation Format: Austin R. Dosch, Xizi Dai, Michelle L. Reyzer, Deukwoo Kwon, Richard Caprioli, Nipun B. Merchant, Nagaraj S. Nagathihalli. Combined Src and EGFR inhibition targets STAT3 to induce stromal remodeling and increase drug delivery to improve survival in a mouse model of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A11.
