期刊
MOLECULAR CANCER THERAPEUTICS
卷 21, 期 5, 页码 810-820出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-21-0550
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资金
- Chicago Biomedical Consortium Accelerator Award [A-013]
- Robert H. Lurie Comprehensive Cancer Research Center - NCI [P30CA060553]
- NCI Ruth L. Kirstenstein fellowship [T32 CA09560]
- SickKids Proof-of-Principal Funding
- Canadian Institutes of Health Research [366017]
This study demonstrates the anticancer activity of RRSP-DTB in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cell lines and patient-derived xenografts (PDX). RRSP-DTB effectively inhibits cell proliferation and induces tumor regression with disrupted tissue architecture, increased fibrosis, and reduced phospho-ERK levels. The study suggests the potential of RRSP-DTB as a promising therapeutic option for RAS-addicted tumors.
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-DTB, an engineered biologic that cleaves the Switch I of all RAS isoforms, in KRAS-mutant PDAC cell lines and patient-derived xenografts (PDX). We first demonstrate that RRSP-DTB effectively engages RAS and impacts downstream ERK signaling in multiple KRAS-mutant PDAC cell lines inhibiting cell proliferation at picomolar concentrations. We next tested RRSP-DTB in immunodeficient mice bearing KRAS-mutant PDAC PDXs. Treatment with RRSP-DTB led to >= 95% tumor regression after 29 days. Residual tumors exhibited disrupted tissue architecture, increased fibrosis and fewer proliferating cells compared with controls. Intra tumoral levels of phospho-ERK were also significantly lower, indicating in vivo target engagement. Importantly, tumors that started to regrow without RRSP-DTB shrank when treatment resumed, demonstrating resistance to RRSP-DT B had not developed. Tracking persistence of the toxin activity following intraperitoneal injection showed that RRSPDTB 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-DTB strongly regresses hard-to-treat KRAS-mutant PDX models of pancreatic cancer, warranting further development of this pan-RAS biologic for the management of RAS-addicted tumors.
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