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adenocarcinomas: Higher susceptibility of women to smoking-related KRAS-mutant cancers","volume":"18","author":"S Dogan","year":"2012","journal-title":"Clin Cancer Res"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1158\/1541-7786.MCR-15-0203","article-title":"Biochemical and structural analysis of common cancer-associated KRAS mutations","volume":"13","author":"JC Hunter","year":"2015","journal-title":"Mol Cancer Res"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1093\/jnci\/djr523","article-title":"Effect of KRAS oncogene substitutions on protein behavior: Implications for signaling and clinical outcome","volume":"104","author":"NT Ihle","year":"2012","journal-title":"J Natl Cancer Inst"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/nchembio.1435","article-title":"Integrated RAS signaling defined by parallel NMR detection of effectors and regulators","volume":"10","author":"MJ 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Tzeng","year":"2012","journal-title":"Nature"},{"key":"ref62","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1146\/annurev-biochem-060614-034142","article-title":"Structure, dynamics, assembly, and evolution of protein complexes","volume":"84","author":"JA Marsh","year":"2015","journal-title":"Annu Rev Biochem"},{"key":"ref63","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1038\/nchem.2785","article-title":"Complete protein-protein association kinetics in atomic detail revealed by molecular dynamics simulations and Markov modelling","volume":"9","author":"N Plattner","year":"2017","journal-title":"Nat Chem"},{"key":"ref64","doi-asserted-by":"crossref","first-page":"7996","DOI":"10.1073\/pnas.1509123112","article-title":"Ras-GTP dimers activate the mitogen-activated protein kinase (MAPK) pathway","volume":"112","author":"X Nan","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"issue":"17","key":"ref65","first-page":"30269","article-title":"Is Nanoclustering essential for all oncogenic KRas pathways? 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