biostudies-literatureKhan IBLRD VANCI NIH HHSNational Institutes of HealthUS Department of Veterans Affairs114-127https://www.ebi.ac.uk/biostudies/studies/S-EPMC9707541biostudies-literatureUnknown13(1)<i>RAS</i> is the most frequently mutated oncogene in human cancer with nearly ~20% of cancer patients possessing mutations in one of three <i>RAS</i> genes (<i>K, N</i> or <i>HRAS</i>). However, <i>KRAS</i> 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 <i>in vitro</i> and <i>in vivo</i> by targeting the α4-α5 allosteric site of RAS and bSmall GTPasesTargeting the KRAS α4-α5 allosteric interface inhibits pancreatic cancer tumorigenesis.PMC9707541P30 CA138313R01 CA2126081I01BX002095CA212608I01 BX002095Zuberi MConnor DMO'Bryan JPOstrowski MCLefler JTimmers CKoide SMarelia-Bennet CKhan IBroome AMDenbaum EKoide APecot TfalseTargeting the KRAS α4-α5 allosteric interface inhibits pancreatic cancer tumorigenesis.<i>RAS</i> is the most frequently mutated oncogene in human cancer with nearly ~20% of cancer patients possessing mutations in one of three <i>RAS</i> genes (<i>K, N</i> or <i>HRAS</i>). However, <i>KRAS</i> 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 <i>in vitro</i> and <i>in vivo</i> by targeting the α4-α5 allosteric site of RAS and b2022-01-01T00:00:00Z2022 Jan2026-06-18T06:59:24.37Z2025-04-06T14:08:34.726ZS-EPMC97075413394991510.1080/21541248.2021.1906621