Data from Proteolytic pan-RAS Cleavage Leads to Tumor Regression in Patient-derived Pancreatic Cancer Xenografts

Abstract

<div>Abstract<p>The lack of effective RAS inhibition represents a major unmet medical need in the treatment of pancreatic ductal adenocarcinoma (PDAC). Here, we investigate the anticancer activity of RRSP-DT<sub>B</sub>, an engineered biologic that cleaves the Switch I of all RAS isoforms, in <i>KRAS</i>-mutant PDAC cell lines and patient-derived xenografts (PDX). We first demonstrate that RRSP-DT<sub>B</sub> effectively engages RAS and impacts downstream ERK signaling in multiple <i>KRAS</i>-mutant PDAC cell lines inhibiting cell proliferation at picomolar concentrations. We next tested RRSP-DT<sub>B</sub> in immunodeficient mice bearing <i>KRAS</i>-mutant PDAC PDXs. Treatment with RRSP-DT<sub>B</sub> led to ≥95% tumor regression after 29 days. Residual tumors exhibited disrupted tissue architecture, increased fibrosis and fewer proliferating cells compared with controls. Intratumoral levels of phospho-ERK were also significantly lower, indicating <i>in vivo</i> target engagement. Importantly, tumors that started to regrow without RRSP-DT<sub>B</sub> shrank when treatment resumed, demonstrating resistance to RRSP-DT<sub>B</sub> had not developed. Tracking persistence of the toxin activity following intraperitoneal injection showed that RRSP-DT<sub>B</sub> is active in sera from immunocompetent mice for at least 1 hour, but absent after 16 hours, justifying use of daily dosing. Overall, we report that RRSP-DT<sub>B</sub> strongly regresses hard-to-treat <i>KRAS</i>-mutant PDX models of pancreatic cancer, warranting further development of this pan-RAS biologic for the management of RAS-addicted tumors.</p></div>