TY - JOUR
T1 - Proteolytic pan-RAS Cleavage Leads to Tumor Regression in Patient-derived Pancreatic Cancer Xenografts
AU - Vidimar, Vania
AU - Park, Minyoung
AU - Stubbs, Caleb K.
AU - Ingram, Nana K.
AU - Qiang, Wenan
AU - Zhang, Shanshan
AU - Gursel, Demirkan
AU - Melnyk, Roman A.
AU - Satchell, Karla J.F.
N1 - Funding Information:
The authors thank B. Shmaltuyeva, B. Frederick, and H. Fan from the Robert H. Lurie Comprehensive Cancer Center Pathology Core Facility for assistance with IHC staining and slide acquisition, the Frederick National Laboratory for Cancer Research (FNLCR) for providing the validated PDAC cell lines and Megan Packer for valuable intellectual input and technical support. This work was funded by a Chicago Biomedical Consortium Accelerator Award (Grant A-013), an H foundation award, and the Robert H. Lurie Comprehensive Cancer Research Center, which is funded by the NCI (Grant P30CA060553). C.K. Stubbs was supported by a NCI Ruth L. Kirstenstein fellowship (T32 CA09560). Additional support from the SickKids Proof-of-Principal Funding and the Canadian Institutes of Health Research Grant 366017 (to R.A. Melnyk).
Funding Information:
V. Vidimar reports other support from Merck Research Laboratories outside the submitted work. C.K. Stubbs reports other support from Aspire Capital Partners, LLC and non-financial support from SmarthHealth Catalyzer Inc. outside the submitted work. R.A. Melnyk reports a patent for US 10,954,520 B2 issued and WO2019104433A1 pending. K.J.F. Satchell reports grants from Chicago Biomedical Consortium, H Foundation, and NCI during the conduct of the study; other support from Situ Biosciences outside the submitted work; in addition, K.J. Satchell has a patent for WO2016019379A1 issued. No disclosures were reported by the other authors.
Publisher Copyright:
©2022 American Association for Cancer Research
PY - 2022/5
Y1 - 2022/5
N2 - 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. Intratumoral 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-DTB had not developed. Tracking persistence of the toxin activity following intraperitoneal injection showed that RRSP-DTB 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.
AB - 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. Intratumoral 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-DTB had not developed. Tracking persistence of the toxin activity following intraperitoneal injection showed that RRSP-DTB 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.
UR - http://www.scopus.com/inward/record.url?scp=85129996625&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129996625&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-21-0550
DO - 10.1158/1535-7163.MCT-21-0550
M3 - Article
C2 - 35247912
AN - SCOPUS:85129996625
SN - 1535-7163
VL - 21
SP - 810
EP - 820
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 5
ER -
