Targeting the KRAS α4-α5 allosteric interface inhibits pancreatic cancer tumorigenesis
Imran Khan1,2,3, Catherine Marelia-Bennet2,4, Julia Lefler2,4
1Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA.
Abstract:
RAS is the most frequently mutated oncogene in human cancer with nearly ~20% of cancer patients possessing mutations in one of three RAS genes (K, N or HRAS). However, KRAS is mutated in nearly 90% of pancreatic ductal carcinomas (PDAC). Although pharmacological inhibition of RAS has been challenging, KRAS(G12C)-specific inhibitors have recently entered the clinic. While KRAS(G12C) is frequently expressed in lung cancers, it is rare in PDAC. Thus, more broadly efficacious RAS inhibitors are needed for treating KRAS mutant-driven cancers such as PDAC. A RAS-specific tool biologic, NS1 Monobody, inhibits HRAS- and KRAS-mediated signalling and oncogenic transformation both in vitro and in vivo by targeting the α4-α5 allosteric site of RAS and blocking RAS self-association. Here, we evaluated the efficacy of targeting the α4-α5 interface of KRAS as an approach to inhibit PDAC development using an immunocompetent orthotopic mouse model. Chemically regulated NS1 expression inhibited ERK and AKT activation in KRAS(G12D) mutant KPC PDAC cells and reduced the formation and progression of pancreatic tumours. NS1-expressing tumours were characterized by increased infiltration of CD4 + T helper cells. These results suggest that targeting the #x3B1;4-#x3B1;5 allosteric site of KRAS may represent a viable therapeutic approach for inhibiting KRAS-mutant pancreatic tumours.
Insights
Targeting the RAS pathway with the NS1 Monobody effectively inhibited pancreatic ductal carcinoma (PDAC) progression in mice. This approach, by blocking KRAS self-association, shows promise for treating KRAS-mutant cancers like PDAC.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- RAS proteins are frequently mutated oncogenes in human cancers, with KRAS mutations prevalent in pancreatic ductal carcinoma (PDAC).
- While KRAS(G12C) inhibitors exist, broadly effective RAS inhibitors are needed for PDAC, where KRAS mutations are common but not typically G12C.
- The NS1 Monobody targets the RAS α4-α5 allosteric site, inhibiting RAS signaling and oncogenic transformation.
Purpose of the Study:
- To evaluate the efficacy of targeting the KRAS α4-α5 interface using the NS1 Monobody in an immunocompetent orthotopic mouse model of PDAC.
- To assess the impact of NS1 Monobody-mediated inhibition on tumor formation, progression, and immune cell infiltration in KRAS-mutant PDAC.
Main Methods:
- Utilized a chemically regulated NS1 expression system in KRAS(G12D) mutant KPC PDAC cells within an orthotopic mouse model.
- Monitored ERK and AKT activation pathways.
- Assessed tumor growth, progression, and CD4+ T helper cell infiltration.
Main Results:
- Chemically induced NS1 expression inhibited ERK and AKT activation in KRAS(G12D) PDAC cells.
- NS1 expression significantly reduced pancreatic tumor formation and progression.
- Tumors with NS1 expression exhibited increased infiltration of CD4+ T helper cells.
Conclusions:
- Targeting the KRAS α4-α5 allosteric site represents a potential therapeutic strategy for KRAS-mutant pancreatic cancer.
- The NS1 Monobody demonstrates efficacy in inhibiting PDAC development and may modulate the tumor immune microenvironment.
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