Functional and biological heterogeneity of KRASQ61mutations

• DOI: 10.1126/scisignal.abn2694
• Publication Date: 2022-08-09T17:57:41Z
• Authors: Minh V. Huynh; G. Aaron Hobbs; Antje Schaefer; Mariaelena Pierobon; Leiah M. Carey; J. Nathaniel Diehl; Jonathan M. DeLib...; Ryan D. Thurman; Adelaide R. Cooke; Craig M. Goodwin; Joshua H. Cook; Lin Lin; Andrew M. Waters; Naim U. Rashid; Emanuel F. Petricoin; Sharon L. Campbell; Kevin M. Haigis; Diane M. Simeone; Costas A. Lyssiotis; Adrienne D. Cox; Channing J. Der
• Keywords: Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); 0301 basic medicine; 03 medical and health sciences; Mutation; Humans; Actins; Carcinoma, Pancreatic Ductal; GTP Phosphohydrolases

Missense mutations at the three hotspots in the guanosine triphosphatase (GTPase) RAS—Gly12, Gly13, and Gln61(commonly known as G12, G13, and Q61, respectively)—occur differentially among the three RAS isoforms. Q61 mutations inKRASare infrequent and differ markedly in occurrence. Q61H is the predominant mutant (at 57%), followed by Q61R/L/K (collectively 40%), and Q61P and Q61E are the rarest (2 and 1%, respectively). Probability analysis suggested that mutational susceptibility to different DNA base changes cannot account for this distribution. Therefore, we investigated whether these frequencies might be explained by differences in the biochemical, structural, and biological properties of KRASQ61mutants. Expression of KRASQ61mutants in NIH 3T3 fibroblasts and RIE-1 epithelial cells caused various alterations in morphology, growth transformation, effector signaling, and metabolism. The relatively rare KRASQ61Emutant stimulated actin stress fiber formation, a phenotype distinct from that of KRASQ61H/R/L/P, which disrupted actin cytoskeletal organization. The crystal structure of KRASQ61Ewas unexpectedly similar to that of wild-type KRAS, a potential basis for its weak oncogenicity. KRASQ61H/L/R-mutant pancreatic ductal adenocarcinoma (PDAC) cell lines exhibited KRAS-dependent growth and, as observed with KRASG12-mutant PDAC, were susceptible to concurrent inhibition of ERK-MAPK signaling and of autophagy. Our results uncover phenotypic heterogeneity among KRASQ61mutants and support the potential utility of therapeutic strategies that target KRASQ61mutant–specific signaling and cellular output.