{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:30:14Z","timestamp":1790105414799,"version":"4.0.1"},"reference-count":95,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T00:00:00Z","timestamp":1728345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373968"],"award-info":[{"award-number":["82373968"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The RAS gene family holds a central position in controlling key cellular activities such as migration, survival, metabolism, and other vital biological processes. The activation of RAS signaling cascades is instrumental in the development of various cancers. Although several RAS inhibitors have gained approval from the US Food and Drug Administration for their substantial antitumor effects, their widespread and severe adverse reactions significantly curtail their practical usage in the clinic. Thus, there exists a pressing need for a comprehensive understanding of these adverse events, ensuring the clinical safety of RAS inhibitors through the establishment of precise management guidelines, suitable intermittent dosing schedules, and innovative combination regimens. This review centers on the evolution of RAS inhibitors in cancer therapy, delving into the common adverse effects associated with these inhibitors, their underlying mechanisms, and the potential strategies for mitigation.<\/jats:p>","DOI":"10.1093\/toxsci\/kfae129","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T16:46:17Z","timestamp":1728405977000},"page":"167-178","source":"Crossref","is-referenced-by-count":1,"title":["Development and safety of investigational and approved drugs targeting the RAS function regulation in RAS mutant cancers"],"prefix":"10.1093","volume":"202","author":[{"given":"Jinjin","family":"Li","sequence":"first","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentong","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifei","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058,","place":["China"]},{"name":"School of Medicine, Hangzhou City University , Hangzhou 310015,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaojun","family":"He","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058,","place":["China"]},{"name":"School of Medicine, Hangzhou City University , Hangzhou 310015,","place":["China"]},{"name":"Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University , Hangzhou 310018,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochun","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058,","place":["China"]},{"name":"Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University , Hangzhou 310018,","place":["China"]},{"name":"Nanhu Brain-Computer Interface Institute , Hangzhou 311100,","place":["China"]},{"name":"Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310018,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Yan","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6576-2052","authenticated-orcid":false,"given":"Peihua","family":"Luo","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou 310058,","place":["China"]},{"name":"Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University , Hangzhou 310018,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,10,8]]},"reference":[{"key":"2024112607504895400_kfae129-B1","author":"Abdel-Wahab"},{"key":"2024112607504895400_kfae129-B2","doi-asserted-by":"crossref","first-page":"183","DOI":"10.12730\/13091719.2019.102.195","article-title":"How could early Christians be wrong? The role of FAHM AL-salaf in the biblical hermeneutics of ibn Taymiyyah and Michael Servetus","volume":"10","author":"Abu Shareea","year":"2019","journal-title":"IS"},{"key":"2024112607504895400_kfae129-B3","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.tips.2024.04.001","article-title":"Malolactone strikes: K-Ras-G12D\u2019s achilles\u2019 heel","volume":"45","author":"Adamopoulos","year":"2024","journal-title":"Trends Pharmacol Sci"},{"key":"2024112607504895400_kfae129-B4","doi-asserted-by":"crossref","first-page":"S458","DOI":"10.1016\/j.annonc.2023.09.1838","article-title":"Preliminary clinical activity of RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor in patients with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC)","volume":"34","author":"Arbour","year":"2023","journal-title":"Annals Oncol"},{"key":"2024112607504895400_kfae129-B5","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.ejmech.2016.01.012","article-title":"PI3K\/akt\/mTOR and ras\/raf\/MEK\/ERK signaling pathways inhibitors as anticancer agents: structural and pharmacological perspectives","volume":"109","author":"Asati","year":"2016","journal-title":"Eur J Med Chem"},{"key":"2024112607504895400_kfae129-B6","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1007\/s00228-022-03287-1","article-title":"Adverse drug reaction management in hospital settings: review on practice variations, quality indicators and education focus","volume":"78","author":"Aung","year":"2022","journal-title":"Eur J Clin Pharmacol"},{"key":"2024112607504895400_kfae129-B7","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1056\/NEJMoa2105281","article-title":"Acquired resistance to KRAS(G12C) inhibition in cancer","volume":"384","author":"Awad","year":"2021","journal-title":"N Engl J Med"},{"key":"2024112607504895400_kfae129-B8","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.3390\/cancers13092152","article-title":"Functional specificity of the members of the Sos family of Ras-GEF activators: novel role of Sos2 in control of epidermal stem cell homeostasis","volume":"13","author":"Baltanas","year":"2021","journal-title":"Cancers"},{"key":"2024112607504895400_kfae129-B9","doi-asserted-by":"crossref","first-page":"S8","DOI":"10.1016\/S0959-8049(20)31089-3","article-title":"Intermittent dosing of RMC-4630, a potent, selective inhibitor of SHP2, combined with the MEK inhibitor cobimetinib, in a phase 1b\/2 clinical trial for advanced solid tumors with activating mutations of RAS signaling","volume":"138","author":"Bendell","year":"2020","journal-title":"Eur J Cancer"},{"key":"2024112607504895400_kfae129-B10","doi-asserted-by":"crossref","first-page":"548","DOI":"10.3390\/antiox12030548","article-title":"Oxidative stress and inflammation in acute and chronic lung injuries","volume":"12","author":"Bezerra","year":"2023","journal-title":"Antioxidants (Basel)"},{"key":"2024112607504895400_kfae129-B11","doi-asserted-by":"crossref","first-page":"S59","DOI":"10.1016\/S0959-8049(22)00958-3","article-title":"Enhancement of anti-tumor immunity in immunogenic and immune-refractory RAS mutant tumors with tri-complex RAS(ON) inhibitors","volume":"174","author":"Blaj","year":"2022","journal-title":"Eur J Cancer"},{"key":"2024112607504895400_kfae129-B12","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1146\/annurev-genom-091416-035332","article-title":"Cognitive dysfunctions in intellectual disabilities: the contributions of the Ras-MAPK and PI3K-AKT-mTOR pathways","volume":"18","author":"Borrie","year":"2017","journal-title":"Annu Rev Genomics Hum Genet"},{"key":"2024112607504895400_kfae129-B13","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1136\/flgastro-2021-101886","article-title":"Guideline review: EASL clinical practice guidelines: drug-induced liver injury (DILI)","volume":"13","author":"Brennan","year":"2022","journal-title":"Frontline Gastroenterol"},{"key":"2024112607504895400_kfae129-B14","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/cpdd.1392","article-title":"Effect of strong CYP3A4 inhibition, CYP3A4 induction, and OATP1B1\/3 inhibition on the pharmacokinetics of a single oral dose of sotorasib","volume":"13","author":"Cardona","year":"2024","journal-title":"Clin Pharmacol Drug Dev"},{"key":"2024112607504895400_kfae129-B15","doi-asserted-by":"crossref","DOI":"10.1002\/cpdd.1452","article-title":"Impact of a high-fat meal on the pharmacokinetics of sotorasib, a KRAS G12C inhibitor","author":"Cardona","year":"2024","journal-title":"Clin Pharmacol Drug Dev"},{"key":"2024112607504895400_kfae129-B16","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s10555-008-9126-y","article-title":"The tyrosine phosphatase Shp2 (PTPN11) in cancer","volume":"27","author":"Chan","year":"2008","journal-title":"Cancer Metastasis Rev"},{"key":"2024112607504895400_kfae129-B17","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1152\/physrev.00003.2012","article-title":"Regulation of small GTPases by GEFs, GAPs, and GDIs","volume":"93","author":"Cherfils","year":"2013","journal-title":"Physiol Rev"},{"key":"2024112607504895400_kfae129-B18","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/S0006-2952(01)00724-9","article-title":"P450 interaction with farnesyl-protein transferase inhibitors\u2014metabolic stability, inhibitory potency, and P450 binding spectra in human liver microsomes","volume":"62","author":"Chiba","year":"2001","journal-title":"Biochem Pharmacol"},{"key":"2024112607504895400_kfae129-B19","first-page":"205","author":"Chou","year":"2022"},{"key":"2024112607504895400_kfae129-B20","doi-asserted-by":"crossref","first-page":"107789","DOI":"10.1016\/j.lungcan.2024.107789","article-title":"Management of sotorasib-related adverse events and hepatotoxicities following anti-PD-(L)1 therapy: experience with sotorasib in two French anti-cancer centers and practical guidance proposal","volume":"191","author":"Chour","year":"2024","journal-title":"Lung Cancer"},{"key":"2024112607504895400_kfae129-B21","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1016\/j.jtho.2023.05.013","article-title":"Brief report: severe sotorasib-related hepatotoxicity and non-liver adverse events associated with sequential anti-programmed cell death (ligand)1 and sotorasib therapy in KRAS(G12C)-mutant lung cancer","volume":"18","author":"Chour","year":"2023","journal-title":"J Thorac Oncol"},{"key":"2024112607504895400_kfae129-B22","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1007\/s40264-021-01109-4","article-title":"Drug-induced liver injury: highlights and controversies in the recent literature","volume":"44","author":"Clinton","year":"2021","journal-title":"Drug Safety"},{"key":"2024112607504895400_kfae129-B23","doi-asserted-by":"crossref","first-page":"e2200211","DOI":"10.1200\/PO.22.00211","article-title":"HRAS mutations define a distinct subgroup in head and neck squamous cell carcinoma","volume":"7","author":"Coleman","year":"2023","journal-title":"JCO Precis Oncol"},{"key":"2024112607504895400_kfae129-B24","first-page":"131","author":"Coley","year":"2022"},{"key":"2024112607504895400_kfae129-B25","doi-asserted-by":"crossref","first-page":"ar9","DOI":"10.1091\/mbc.E22-06-0236","article-title":"Ras-mediated activation of mTORC2 promotes breast epithelial cell migration and invasion","volume":"34","author":"Collins","year":"2023","journal-title":"Mol Biol Cell"},{"key":"2024112607504895400_kfae129-B26","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/S0968-0004(01)01974-0","article-title":"The many faces of Ras: recognition of small GTP-binding proteins","volume":"26","author":"Corbett","year":"2001","journal-title":"Trends Biochem Sci"},{"key":"2024112607504895400_kfae129-B27","doi-asserted-by":"crossref","first-page":"266","DOI":"10.2174\/0929867330666230330122000","article-title":"First approval of adagrasib for the treatment of non-small cell lung cancer harboring a KRASG12C mutation","volume":"31","author":"De","year":"2024","journal-title":"Curr Med Chem"},{"key":"2024112607504895400_kfae129-B28","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.therap.2023.10.008","article-title":"Drug-induced cardiac toxicity and adverse drug reactions, a narrative review","volume":"79","author":"Destere","year":"2024","journal-title":"Therapie"},{"key":"2024112607504895400_kfae129-B29","doi-asserted-by":"crossref","first-page":"e30437","DOI":"10.1016\/j.heliyon.2024.e30437","article-title":"Post-marketing safety concerns of sotorasib: a disproportionality analysis based on FDA adverse event reporting system","volume":"10","author":"Ding","year":"2024","journal-title":"Heliyon"},{"key":"2024112607504895400_kfae129-B30","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1158\/1538-7445.AM2020-1091","article-title":"BI-3406 and BI 1701963: potent and selective SOS1: KRAS inhibitors induce regressions in combination with MEK inhibitors or irinotecan","volume":"80","author":"Gerlach","year":"2020","journal-title":"Cancer Res"},{"key":"2024112607504895400_kfae129-B31","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0041-3879(77)90022-8","article-title":"The hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide","volume":"59","author":"Girling","year":"1978","journal-title":"Tubercle"},{"key":"2024112607504895400_kfae129-B32","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1200\/JCO.2022.40.4_suppl.591","article-title":"Direct targeting of RAS in pancreatic ductal adenocarcinoma with RMC-6236, a first-in-class, RAS-selective, orally bioavailable, tri-complex RASMULTI(ON) inhibitor","volume":"40","author":"Gustafson","year":"2022","journal-title":"J Clin Oncol"},{"key":"2024112607504895400_kfae129-B33","doi-asserted-by":"crossref","first-page":"102195","DOI":"10.1016\/j.esmoop.2023.102195","article-title":"2023 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting","volume":"9","author":"Herrstedt","year":"2024","journal-title":"ESMO Open"},{"key":"2024112607504895400_kfae129-B34","doi-asserted-by":"crossref","first-page":"S468","DOI":"10.1016\/j.annonc.2023.09.1851","article-title":"First-in-human, phase Ia\/b, dose-escalation\/expansion study of KRAS G12C inhibitor BI 1823911, as monotherapy and combined with anticancer therapies, in patients (pts) with advanced or metastatic solid tumours harbouring a KRAS G12C mutation","volume":"34","author":"Heymach","year":"2023","journal-title":"Anna Oncol"},{"key":"2024112607504895400_kfae129-B35","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1038\/s41586-024-07205-6","article-title":"Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy","volume":"629","author":"Holderfield","year":"2024","journal-title":"Nature"},{"key":"2024112607504895400_kfae129-B36","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1210\/jc.2010-1899","article-title":"Inhibition of the Ras\/Raf\/MEK\/ERK and RET kinase pathways with the combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in medullary and differentiated thyroid malignancies","volume":"96","author":"Hong","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"2024112607504895400_kfae129-B37","doi-asserted-by":"crossref","first-page":"17562848231163410","DOI":"10.1177\/17562848231163410","article-title":"Drug-induced liver injury: a comprehensive review","volume":"16","author":"Hosack","year":"2023","journal-title":"Therap Adv Gastroenterol"},{"key":"2024112607504895400_kfae129-B38","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1158\/1535-7163.MCT-17-0666","article-title":"Small molecule-mediated activation of RAS elicits biphasic modulation of phospho-ERK levels that are regulated through negative feedback on SOS1","volume":"17","author":"Howes","year":"2018","journal-title":"Mol Cancer Ther"},{"key":"2024112607504895400_kfae129-B39","doi-asserted-by":"crossref","DOI":"10.1158\/1535-7163.TARG-23-PR014","article-title":"Preliminary safety and anti-tumor activity of RMC-6291, a first-in-class, tri-complex KRASG12C(ON) inhibitor, in patients with or without prior KRASG12C(OFF) inhibitor treatment","volume":"22","author":"J\u00e4nne","year":"2023","journal-title":"Mol Cancer Ther"},{"key":"2024112607504895400_kfae129-B40","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1158\/2159-8290.CD-24-0027","article-title":"Translational and therapeutic evaluation of RAS-GTP inhibition by RMC-6236 in RAS-Driven cancers","volume":"14","author":"Jiang","year":"2024","journal-title":"Cancer Discov"},{"key":"2024112607504895400_kfae129-B41","doi-asserted-by":"crossref","first-page":"S591","DOI":"10.1016\/j.annonc.2021.08.1046","article-title":"A phase I, open-label, dose-escalation trial of BI 1701963 in patients (pts) with KRAS mutated solid tumours: a snapshot analysis","volume":"32","author":"Johnson","year":"2021","journal-title":"Anna Oncol"},{"key":"2024112607504895400_kfae129-B42","first-page":"591","article-title":"Comparitive analysis of signal transduction pathways between thrombopoietin and erythropoietin involves Ras- and JAK-STAT-mediated signalings","volume":"86","author":"Katagiri","year":"1995","journal-title":"Blood"},{"key":"2024112607504895400_kfae129-B43","doi-asserted-by":"crossref","first-page":"9678","DOI":"10.1021\/acs.jmedchem.2c00741","article-title":"Design and discovery of MRTX0902, a potent, selective, brain-penetrant, and orally bioavailable inhibitor of the SOS1: KRAS protein-protein interaction","volume":"65","author":"Ketcham","year":"2022","journal-title":"J Med Chem"},{"key":"2024112607504895400_kfae129-B44","doi-asserted-by":"crossref","DOI":"10.1158\/1538-7445.AM2022-ND02","article-title":"MRTX0902: a SOS1 inhibitor for therapeutic intervention of KRAS-driven cancers","volume":"82","author":"Ketcham","year":"2022","journal-title":"Cancer Res."},{"key":"2024112607504895400_kfae129-B45","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41416-019-0523-5","article-title":"Enhanced antitumor effect of binimetinib in combination with capecitabine for biliary tract cancer patients with mutations in the RAS\/RAF\/MEK\/ERK pathway: phase Ib study","volume":"121","author":"Kim","year":"2019","journal-title":"Br J Cancer"},{"key":"2024112607504895400_kfae129-B46","doi-asserted-by":"crossref","first-page":"LB001","DOI":"10.1158\/1538-7445.AM2021-LB001","article-title":"Anti-tumor activity and tolerability of the SHP2 inhibitor RMC-4630 as a single agent in patients with RAS-addicted solid cancers","volume":"81","author":"Koczywas","year":"2021","journal-title":"Cancer Res"},{"key":"2024112607504895400_kfae129-B47","author":"Lennek","year":"2020"},{"key":"2024112607504895400_kfae129-B48","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1073\/pnas.1413185112","article-title":"Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices","volume":"112","author":"Leshchiner","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024112607504895400_kfae129-B49","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/j.jtho.2023.03.015","article-title":"D-1553 (garsorasib), a potent and selective inhibitor of KRASG12C in patients with NSCLC: phase 1 study results","volume":"18","author":"Li","year":"2023","journal-title":"J Thoracic Oncol"},{"key":"2024112607504895400_kfae129-B50","doi-asserted-by":"crossref","first-page":"2927","DOI":"10.1016\/j.apsb.2024.03.002","article-title":"In silico off-target profiling for enhanced drug safety assessment","volume":"14","author":"Liu","year":"2024","journal-title":"Acta Pharmaceutica Sinica B"},{"key":"2024112607504895400_kfae129-B51","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.1038\/s41467-022-30392-7","article-title":"Rapid acceleration of KRAS-mutant pancreatic carcinogenesis via remodeling of tumor immune microenvironment by PPAR\u03b4","volume":"13","author":"Liu","year":"2022","journal-title":"Nat Commun"},{"key":"2024112607504895400_kfae129-B52","doi-asserted-by":"crossref","first-page":"4587","DOI":"10.1158\/1078-0432.CCR-21-0180","article-title":"Clinical and functional characterization of atypical KRAS\/NRAS mutations in metastatic colorectal cancer","volume":"27","author":"Loree","year":"2021","journal-title":"Clin Cancer Res"},{"key":"2024112607504895400_kfae129-B53","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S0092-8674(03)00149-1","article-title":"Structural evidence for feedback activation by Ras-GTP of the Ras-specific nucleotide exchange factor SOS","volume":"112","author":"Margarit","year":"2003","journal-title":"Cell"},{"key":"2024112607504895400_kfae129-B54","doi-asserted-by":"crossref","DOI":"10.1158\/1538-7445.AM2023-CT184","article-title":"Preliminary dose escalation results of ERAS-601 in combination with cetuximab in FLAGSHP-1: a phase I study of ERAS-601, a potent and selective SHP2 inhibitor, in patients with previously treated advanced or metastatic solid tumors","volume":"83","author":"McKean","year":"2023","journal-title":"Cancer Res."},{"key":"2024112607504895400_kfae129-B55","doi-asserted-by":"crossref","first-page":"498","DOI":"10.2174\/1871520622666220921093052","article-title":"Small-molecule modulators targeting SHP2 for cancer therapy","volume":"23","author":"Mi","year":"2023","journal-title":"Anti-Cancer Agents Med Chem"},{"key":"2024112607504895400_kfae129-B56","doi-asserted-by":"crossref","first-page":"CT028","DOI":"10.1158\/1538-7445.AM2023-CT028","article-title":"A first-in-human phase 1 study of LY3537982, a highly selective and potent KRAS G12C inhibitor in patients with KRAS G12C-mutant advanced solid tumors","volume":"83","author":"Murciano-Goroff","year":"2023","journal-title":"Cancer Res"},{"key":"2024112607504895400_kfae129-B57","doi-asserted-by":"crossref","first-page":"3595","DOI":"10.1158\/1538-7445.AM2022-3595","article-title":"RMC-6291, a next-generation tri-complex KRASG12C(ON) inhibitor, outperforms KRASG12C(OFF) inhibitors in preclinical models of KRASG12C cancers","volume":"82","author":"Nichols","year":"2022","journal-title":"Cancer Res"},{"key":"2024112607504895400_kfae129-B58","doi-asserted-by":"crossref","first-page":"2973","DOI":"10.1038\/s41388-022-02305-x","article-title":"Targeting farnesylation as a novel therapeutic approach in HRAS-mutant rhabdomyosarcoma","volume":"41","author":"Odeniyide","year":"2022","journal-title":"Oncogene"},{"key":"2024112607504895400_kfae129-B59","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1080\/21541248.2021.1896963","article-title":"GPCRs that rhoar the guanine nucleotide exchange factors","volume":"13","author":"Omble","year":"2022","journal-title":"Small GTPases"},{"key":"2024112607504895400_kfae129-B60","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12104-019-09909-7","article-title":"1H, 15N backbone assignment and comparative analysis of the wild type and G12C, G12D, G12V mutants of K-Ras bound to GDP at physiological pH","volume":"14","author":"P\u00e1lfy","year":"2020","journal-title":"Biomol NMR Assign"},{"key":"2024112607504895400_kfae129-B61","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.critrevonc.2018.07.011","article-title":"Clinical update on K-Ras targeted therapy in gastrointestinal cancers","volume":"130","author":"Pant","year":"2018","journal-title":"Crit Rev Oncol Hematol"},{"key":"2024112607504895400_kfae129-B62","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1158\/1538-7445.AM2021-1259","article-title":"Preclinical characterization of LY3537982, a novel, highly selective and potent KRAS-G12C inhibitor","volume":"81","author":"Peng","year":"2021","journal-title":"Cancer Res."},{"key":"2024112607504895400_kfae129-B63","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/s41408-019-0183-y","article-title":"Management of cardiovascular risk in patients with multiple myeloma","volume":"9","author":"Plummer","year":"2019","journal-title":"Blood Cancer J"},{"key":"2024112607504895400_kfae129-B64","doi-asserted-by":"crossref","first-page":"2969","DOI":"10.1158\/0008-5472.CAN-19-3682","article-title":"The frequency of Ras mutations in cancer","volume":"80","author":"Prior","year":"2020","journal-title":"Cancer Res"},{"key":"2024112607504895400_kfae129-B65","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/s41571-022-00671-9","article-title":"The current state of the art and future trends in RAS-targeted cancer therapies","volume":"19","author":"Punekar","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"key":"2024112607504895400_kfae129-B66","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/ng1926","article-title":"Germline gain-of-function mutations in SOS1 cause noonan syndrome","volume":"39","author":"Roberts","year":"2007","journal-title":"Nat Gene"},{"key":"2024112607504895400_kfae129-B67","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.lungcan.2021.12.021","article-title":"Targeting KRAS G12C mutation in lung adenocarcinoma","volume":"165","author":"Rohatgi","year":"2022","journal-title":"Lung Cancer"},{"key":"2024112607504895400_kfae129-B68","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/360689a0","article-title":"Association of the Shc and Grb2\/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases","volume":"360","author":"Rozakis-Adcock","year":"1992","journal-title":"Nature"},{"key":"2024112607504895400_kfae129-B69","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.7150\/thno.79493","article-title":"Non-canonical integrin signaling activates EGFR and RAS-MAPK-ERK signaling in small cell lung cancer","volume":"13","author":"Rubio","year":"2023","journal-title":"Theranostics"},{"key":"2024112607504895400_kfae129-B70","doi-asserted-by":"crossref","first-page":"100186","DOI":"10.1016\/j.xcrm.2020.100186","article-title":"The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC)","volume":"2","author":"Salgia","year":"2021","journal-title":"Cell Rep Med"},{"key":"2024112607504895400_kfae129-B71","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.4103\/jcrt.JCRT_624_20","article-title":"Induction of apoptosis and suppression of Ras gene expression in MCF human breast cancer cells","volume":"18","author":"Saremi","year":"2022","journal-title":"J Cancer Res Ther"},{"key":"2024112607504895400_kfae129-B72","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1158\/1538-7445.AM2021-1271","article-title":"In vitro and in vivo characterization of BI 1823911-a novel KRASG12C selective small molecule inhibitor","volume":"81","author":"Savarese","year":"2021","journal-title":"Cancer Res"},{"key":"2024112607504895400_kfae129-B73","first-page":"29","article-title":"KontRASt-01: a phase Ib\/II dose escalation study of JDQ443 in patients with advanced KRAS G12C mutated solid tumors","volume":"45","author":"Schuler","year":"2022","journal-title":"Oncol Res Treat"},{"key":"2024112607504895400_kfae129-B74","doi-asserted-by":"crossref","first-page":"2951","DOI":"10.1111\/cas.15829","article-title":"D-1553: a novel KRAS(G12C) inhibitor with potent and selective cellular and in vivo antitumor activity","volume":"114","author":"Shi","year":"2023","journal-title":"Cancer Sci"},{"key":"2024112607504895400_kfae129-B75","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.cell.2017.06.009","article-title":"RAS proteins and their regulators in human disease","volume":"170","author":"Simanshu","year":"2017","journal-title":"Cell"},{"key":"2024112607504895400_kfae129-B76","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1042\/BST20200506","article-title":"RAS GTPase signalling to alternative effector pathways","volume":"48","author":"Singh","year":"2020","journal-title":"Biochem Soc Trans"},{"key":"2024112607504895400_kfae129-B77","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1056\/NEJMoa2103695","article-title":"Sotorasib for lung cancers with KRAS p.G12C mutation","volume":"384","author":"Skoulidis","year":"2021","journal-title":"N Engl J Med"},{"key":"2024112607504895400_kfae129-B78","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.cell.2004.10.005","article-title":"Structural analysis of autoinhibition in the Ras activator son of sevenless","volume":"119","author":"Sondermann","year":"2004","journal-title":"Cell"},{"key":"2024112607504895400_kfae129-B79","doi-asserted-by":"crossref","first-page":"PR010","DOI":"10.1158\/1535-7163.TARG-23-PR010","article-title":"Preliminary safety and pharmacokinetic profiles of RMC-6236, a first-in-class, RAS-selective, tri-complex RASMULTI(ON) inhibitor in patients with KRAS mutant solid tumors on the phase 1 trial RMC-6236-001","volume":"22","author":"Spira","year":"2023","journal-title":"Mol Cancer Ther"},{"key":"2024112607504895400_kfae129-B80","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1158\/1535-7163.MCT-23-0870","article-title":"The SOS1 inhibitor MRTX0902 blocks KRAS activation and demonstrates antitumor activity in cancers dependent on KRAS nucleotide loading","volume":"23","author":"Sudhakar","year":"2024","journal-title":"Mol Cancer Ther"},{"key":"2024112607504895400_kfae129-B81","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1080\/13543776.2021.1952984","article-title":"Small molecule son of sevenless 1 (SOS1) inhibitors: a review of the patent literature","volume":"31","author":"Thompson","year":"2021","journal-title":"Exp Opin Thera Patents"},{"key":"2024112607504895400_kfae129-B82","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1158\/2159-8290.CD-18-0915","article-title":"Shipping out MeK inhibitor resistance with sHP2 inhibitors","volume":"8","author":"Torres-Ayuso","year":"2018","journal-title":"Cancer Discovery"},{"key":"2024112607504895400_kfae129-B83","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3390\/gastroent15010014","article-title":"GLP-1RA essentials in gastroenterology: side effect management, precautions for endoscopy and applications for gastrointestinal disease treatment","volume":"15","author":"Wan","year":"2024","journal-title":"Gastroenterol Insights"},{"key":"2024112607504895400_kfae129-B84","doi-asserted-by":"crossref","first-page":"S459","DOI":"10.1016\/j.annonc.2023.09.1839","article-title":"Glecirasib (KRAS G12C inhibitor) in combination with JAB-3312 (SHP2 inhibitor) in patients with KRAS p.G12C mutated solid tumors","volume":"34","author":"Wang","year":"2023","journal-title":"Anna Oncol"},{"key":"2024112607504895400_kfae129-B85","doi-asserted-by":"crossref","first-page":"114325","DOI":"10.1016\/j.biopha.2023.114325","article-title":"Cross-talk between the RAS-ERK and mTOR signalings-associated autophagy contributes to tripterygium glycosides tablet-induced liver injury","volume":"160","author":"Wang","year":"2023","journal-title":"Biomed Pharmacother"},{"key":"2024112607504895400_kfae129-B86","doi-asserted-by":"crossref","first-page":"114325","DOI":"10.1016\/j.biopha.2023.114325","article-title":"Cross-talk between the RAS-ERK and mTOR signalings-associated autophagy contributes to tripterygium glycosides tablet-induced liver injury","volume":"160","author":"Wang","year":"2023","journal-title":"Biomed Pharmacother"},{"key":"2024112607504895400_kfae129-B87","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1158\/2159-8290.CD-22-0158","article-title":"Discovery, preclinical characterization, and early clinical activity of JDQ443, a structurally novel, potent, and selective covalent oral inhibitor of KRASG12C","volume":"12","author":"Weiss","year":"2022","journal-title":"Cancer Discovs"},{"key":"2024112607504895400_kfae129-B88","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.cell.2017.02.006","article-title":"Multivalent small-molecule Pan-RAS inhibitors","volume":"168","author":"Welsch","year":"2017","journal-title":"Cell"},{"key":"2024112607504895400_kfae129-B89","doi-asserted-by":"crossref","first-page":"739","DOI":"10.18632\/oncoscience.188","article-title":"Tumorigenicity of RTK\/RAS in urothelium","volume":"2","author":"Wu","year":"2015","journal-title":"Oncoscience"},{"key":"2024112607504895400_kfae129-B90","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1056\/NEJMoa2212419","article-title":"Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C","volume":"388","author":"Yaeger","year":"2023","journal-title":"N Engl J Med"},{"key":"2024112607504895400_kfae129-B91","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.cell.2019.01.002","article-title":"Pharmacological targeting of STK19 inhibits oncogenic NRAS-driven melanomagenesis","volume":"176","author":"Yin","year":"2019","journal-title":"Cell"},{"key":"2024112607504895400_kfae129-B92","doi-asserted-by":"crossref","first-page":"101448","DOI":"10.1016\/j.isci.2020.101448","article-title":"KRAS ubiquitination at lysine 104 retains exchange factor regulation by dynamically modulating the conformation of the interface","volume":"23","author":"Yin","year":"2020","journal-title":"IScience"},{"key":"2024112607504895400_kfae129-B93","author":"Zhao","year":"2006"},{"key":"2024112607504895400_kfae129-B94","doi-asserted-by":"crossref","first-page":"S1273","DOI":"10.1016\/j.annonc.2023.10.025","article-title":"A first-in-human phase I study of a novel KRAS G12D inhibitor HRS-4642 in patients with advanced solid tumors harboring KRAS G12D mutation","volume":"34","author":"Zhou","year":"2023","journal-title":"Anna Oncol"},{"key":"2024112607504895400_kfae129-B95","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1186\/s12943-021-01441-4","article-title":"Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer","volume":"20","author":"Zhu","year":"2021","journal-title":"Mol Cancer"}],"container-title":["Toxicological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/toxsci\/advance-article-pdf\/doi\/10.1093\/toxsci\/kfae129\/59813453\/kfae129.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/202\/2\/167\/60807895\/kfae129.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/202\/2\/167\/60807895\/kfae129.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T07:51:27Z","timestamp":1732607487000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxsci\/article\/202\/2\/167\/7815736"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,8]]},"references-count":95,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,10,8]]},"published-print":{"date-parts":[[2024,12,1]]}},"URL":"https:\/\/doi.org\/10.1093\/toxsci\/kfae129","relation":{},"ISSN":["1096-6080","1096-0929"],"issn-type":[{"value":"1096-6080","type":"print"},{"value":"1096-0929","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,12]]},"published":{"date-parts":[[2024,10,8]]}}}