Targeting the KRAS α4-α5 allosteric interface inhibits pancreatic cancer tumorigenesis
| Autor: | Michael C. Ostrowski, Catherine MarElia-Bennet, Cynthia J. Timmers, Akiko Koide, John P. O'Bryan, Mariyam Zuberi, Julia E. Lefler, Thierry Pécot, Eric Denbaum, Dean M. Connor, Imran Khan, Ann-Marie Broome, Shohei Koide |
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| Rok vydání: | 2021 |
| Předmět: |
MAPK/ERK pathway
endocrine system diseases Carcinogenesis T cell Biology medicine.disease_cause Biochemistry Proto-Oncogene Proteins p21(ras) Mice 03 medical and health sciences 0302 clinical medicine Pancreatic cancer medicine Animals Humans HRAS neoplasms 030304 developmental biology 0303 health sciences Oncogene Cancer Cell Biology medicine.disease digestive system diseases Cell biology Pancreatic Neoplasms medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research KRAS Carcinoma Pancreatic Ductal Research Paper |
| Zdroj: | Small GTPases |
| ISSN: | 2154-1256 2154-1248 |
| DOI: | 10.1080/21541248.2021.1906621 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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