{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T20:32:06Z","timestamp":1771878726669,"version":"3.50.1"},"reference-count":46,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T00:00:00Z","timestamp":1653004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Introduction: Assessment of actionable gene mutations and oncogene fusions have made a paradigm shift in treatment strategies of non-small cell lung cancer (NSCLC). HRAS mutations involved around 0.2\u20130.8% of NSCLC patients, mostly on codon 61. For these patients, few data are available regarding clinical characteristics and response to therapies. Methods: Next-Generation Sequencing (NGS) done routinely at Nantes University Hospital was used to identify HRAS molecular alterations in NSCLC patients. We identified and described four HRAS p.GlnQ61Leu mutated patients. Literature of previously HRAS-mutant NSCLC cases was reviewed, and available data in solid tumour with the most advanced H-Ras specific inhibitor, tipifarnib, were presented. Results: Of 1614 patients diagnosed with advanced NSCLC from January 2018 to December 2020, four (0.25%) had HRAS p.Gln61Leu mutation. Three of them died during the first-line systemic therapy. Furthermore, three additional cases were identified in literature. All cases were current or former smokers, most of them had pleural or pericardial effusion at diagnosis. Conclusions: The clinical course of patients with HRAS-mutant NSCLC remains unclear. Furthers cases should be identified in order to clarify prognosis and response to therapies. Tipifarnib, a farnesyl transferase inhibitor, is a promising candidate to target HRAS-mutant tumours and should be explored in NSCLC patients.<\/jats:p>","DOI":"10.3390\/curroncol29050300","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T13:56:12Z","timestamp":1653054972000},"page":"3748-3758","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["HRAS Q61L Mutation as a Possible Target for Non-Small Cell Lung Cancer: Case Series and Review of Literature"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8601-1226","authenticated-orcid":false,"given":"Laurent","family":"Mathiot","sequence":"first","affiliation":[{"name":"Service d\u2019Oncologie M\u00e9dicale, CHU Nantes, Nantes Universit\u00e9, F-44000 Nantes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3705-2114","authenticated-orcid":false,"given":"Guillaume","family":"Herbreteau","sequence":"additional","affiliation":[{"name":"UMR 1302\/EMR6001, INCIT, Immunology and New Concepts in ImmunoTherapy, CNRS, INSERM, Laboratoire de Biochimie, CHU Nantes, Nantes Universit\u00e9, F-44000 Nantes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sim\u00e9on","family":"Robin","sequence":"additional","affiliation":[{"name":"Pharmacie, CHU Nantes, Nantes Universit\u00e9, F-44000 Nantes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte","family":"Fenat","sequence":"additional","affiliation":[{"name":"Pharmacie, CHU Nantes, Nantes Universit\u00e9, F-44000 Nantes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaafar","family":"Bennouna","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hospital Foch, F-92073 Suresnes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0917-3747","authenticated-orcid":false,"given":"Christophe","family":"Blanquart","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, Inserm UMR 1307, CNRS UMR 6075, Universit\u00e9 d\u2019Angers, CRCI2NA, F-44000 Nantes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5865-3248","authenticated-orcid":false,"given":"Marc","family":"Denis","sequence":"additional","affiliation":[{"name":"UMR 1302\/EMR6001, INCIT, Immunology and New Concepts in ImmunoTherapy, CNRS, INSERM, Laboratoire de Biochimie, CHU Nantes, Nantes Universit\u00e9, F-44000 Nantes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4478-0523","authenticated-orcid":false,"given":"Elvire","family":"Pons-Tostivint","sequence":"additional","affiliation":[{"name":"Service d\u2019Oncologie M\u00e9dicale, CHU Nantes, Nantes Universit\u00e9, F-44000 Nantes, France"},{"name":"Nantes Universit\u00e9, Inserm UMR 1307, CNRS UMR 6075, Universit\u00e9 d\u2019Angers, CRCI2NA, F-44000 Nantes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1056\/NEJMoa040938","article-title":"Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib","volume":"350","author":"Lynch","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1056\/NEJMoa1913662","article-title":"Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC","volume":"382","author":"Ramalingam","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1056\/NEJMoa1704795","article-title":"Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer","volume":"377","author":"Peters","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1056\/NEJMoa1810171","article-title":"Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer","volume":"379","author":"Camidge","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1056\/NEJMoa2027187","article-title":"First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer","volume":"383","author":"Shaw","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1056\/NEJMoa1406766","article-title":"Crizotinib in ROS1-Rearranged Non-Small-Cell Lung Cancer","volume":"371","author":"Shaw","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1056\/NEJMoa1917239","article-title":"KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors","volume":"383","author":"Hong","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/s41571-018-0105-0","article-title":"Therapeutic Strategies to Target RAS-Mutant Cancers","volume":"15","author":"Ryan","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/nrc3106","article-title":"RAS Oncogenes: Weaving a Tumorigenic Web","volume":"11","author":"Grabocka","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2","DOI":"10.4161\/sgtp.1.1.12178","article-title":"Ras History: The Saga Continues","volume":"1","author":"Cox","year":"2010","journal-title":"Small GTPases"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nrm2438","article-title":"Ras Oncogenes: Split Personalities","volume":"9","author":"Karnoub","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_13","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":"ref_14","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/nm.4333","article-title":"Mutational Landscape of Metastatic Cancer Revealed from Prospective Clinical Sequencing of 10,000 Patients","volume":"23","author":"Zehir","year":"2017","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.bbrc.2021.05.084","article-title":"Oncogenic Mutations Q61L and Q61H Confer Active Form-Like Structural Features to the Inactive State (State 1) Conformation of H-Ras Protein","volume":"565","author":"Matsumoto","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105806","DOI":"10.1016\/j.phrs.2021.105806","article-title":"Blockade of Mutant RAS Oncogenic Signaling with a Special Emphasis on KRAS","volume":"172","author":"Roskoski","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e75","DOI":"10.1097\/JTO.0000000000000315","article-title":"Elderly Former Smoker with HRAS Mutant Non-Small-Cell Lung Cancer","volume":"9","author":"Corless","year":"2014","journal-title":"J. Thorac. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.2147\/OTT.S295813","article-title":"Poor Prognosis of Pulmonary Adenosquamous Carcinoma with NRAS and HRAS Double Mutation","volume":"14","author":"Zhao","year":"2021","journal-title":"Onco Targets Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7088","DOI":"10.21037\/apm-20-1639","article-title":"The Influence of STK11 Mutation on Acquired Resistance to Immunotherapy in Advanced Non-Small Cell Lung Cancer with Lynch Syndrome: A Case Report and Literature Review","volume":"10","author":"Long","year":"2021","journal-title":"Ann. Palliat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"The Cancer Genome Atlas Research Network (2014). Comprehensive Molecular Profiling of Lung Adenocarcinoma. Nature, 511, 543\u2013550.","DOI":"10.1038\/nature13385"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5961","DOI":"10.1038\/s41467-021-26213-y","article-title":"Cancer Gene Mutation Frequencies for the U.S. Population","volume":"12","author":"Mendiratta","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nature11404","article-title":"Comprehensive Genomic Characterization of Squamous Cell Lung Cancers","volume":"489","author":"Hammerman","year":"2012","journal-title":"Nature"},{"key":"ref_23","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":"ref_24","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/nature14129","article-title":"Comprehensive Genomic Characterization of Head and Neck Squamous Cell Carcinomas","volume":"517","author":"Lawrence","year":"2015","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/nature12965","article-title":"Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma","volume":"507","author":"Weinstein","year":"2014","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.semcancer.2018.03.001","article-title":"RAS-Mediated Oncogenic Signaling Pathways in Human Malignancies","volume":"54","author":"Khan","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.cell.2017.09.007","article-title":"Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer","volume":"171","author":"Robertson","year":"2017","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1002\/gcc.22347","article-title":"HRAS Mutation Prevalence and Associated Expression Patterns in Pheochromocytoma","volume":"55","author":"Stenman","year":"2016","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1016\/j.juro.2007.12.040","article-title":"PIK3CA, HRAS and KRAS Gene Mutations in Human Penile Cancer","volume":"179","author":"Andersson","year":"2008","journal-title":"J. Urol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"42183","DOI":"10.18632\/oncotarget.5619","article-title":"Mutant HRAS as Novel Target for MEK and MTOR Inhibitors","volume":"6","author":"Kiessling","year":"2015","journal-title":"Oncotarget"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1158\/1535-7163.MCT-19-0958","article-title":"Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas","volume":"19","author":"Gilardi","year":"2020","journal-title":"Mol. Cancer Ther."},{"key":"ref_32","first-page":"131","article-title":"Characterization of the Antitumor Effects of the Selective Farnesyl Protein Transferase Inhibitor R115777 In Vivo and In Vitro","volume":"61","author":"End","year":"2001","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/s41573-020-0068-6","article-title":"RAS-Targeted Therapies: Is the Undruggable Drugged?","volume":"19","author":"Moore","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"14459","DOI":"10.1074\/jbc.272.22.14459","article-title":"K- and N-Ras Are Geranylgeranylated in Cells Treated with Farnesyl Protein Transferase Inhibitors","volume":"272","author":"Whyte","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Liu, J., Kang, R., and Tang, D. (2021). The KRAS-G12C Inhibitor: Activity and Resistance. Cancer Gene Ther., 1\u20134.","DOI":"10.1038\/s41417-021-00383-9"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1200\/JCO.20.02903","article-title":"Tipifarnib in Head and Neck Squamous Cell Carcinoma With HRAS Mutations","volume":"39","author":"Ho","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3972","DOI":"10.1002\/cncr.33036","article-title":"Tipifarnib in Recurrent, Metastatic HRAS-Mutant Salivary Gland Cancer","volume":"126","author":"Hanna","year":"2020","journal-title":"Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5113","DOI":"10.1158\/1078-0432.CCR-20-1246","article-title":"A Phase II Trial of Tipifarnib for Patients with Previously Treated, Metastatic Urothelial Carcinoma Harboring HRAS Mutations","volume":"26","author":"Lee","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s10637-018-0662-1","article-title":"A Phase I Study of the Farnesyltransferase Inhibitor Tipifarnib in Combination with the Epidermal Growth Factor Tyrosine Kinase Inhibitor Erlotinib in Patients with Advanced Solid Tumors","volume":"37","author":"Jazieh","year":"2019","journal-title":"Investig. New Drugs"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/s10637-005-4345-3","article-title":"Phase II Trial of R115777 (NSC #70818) in Patients with Advanced Colorectal Cancer: A Southwest Oncology Group Study","volume":"24","author":"Whitehead","year":"2006","journal-title":"Investig. New Drugs"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1097\/00001813-200503000-00011","article-title":"Intermittent Dosing of the Farnesyl Transferase Inhibitor Tipifarnib (R115777) in Advanced Malignant Solid Tumors: A Phase I California Cancer Consortium Trial","volume":"16","author":"Lara","year":"2005","journal-title":"Anti-Cancer Drugs"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1093\/annonc\/mdh315","article-title":"Phase II Study of the Farnesyl Transferase Inhibitor R115777 in Patients with Sensitive Relapse Small-Cell Lung Cancer","volume":"15","author":"Heymach","year":"2004","journal-title":"Ann. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1200\/JCO.2003.09.075","article-title":"Phase II Study of the Farnesyl Transferase Inhibitor R115777 in Patients with Advanced Non-Small-Cell Lung Cancer","volume":"21","author":"Adjei","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_44","first-page":"1065","article-title":"A Phase I Trial of the Farnesyltransferase Inhibitor L-778,123 and Radiotherapy for Locally Advanced Lung and Head and Neck Cancer","volume":"8","author":"Hahn","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/s41557-019-0237-6","article-title":"Dual Chemical Probes Enable Quantitative System-Wide Analysis of Protein Prenylation and Prenylation Dynamics","volume":"11","author":"Storck","year":"2019","journal-title":"Nat. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"CT191","DOI":"10.1158\/1538-7445.AM2019-CT191","article-title":"Abstract CT191: Mechanism of Action of the Farnesyltransferase Inhibitor, Tipifarnib and Its Clinical Applications","volume":"79","author":"Gualberto","year":"2019","journal-title":"Cancer Res."}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/29\/5\/300\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:15:38Z","timestamp":1760138138000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/29\/5\/300"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,20]]},"references-count":46,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["curroncol29050300"],"URL":"https:\/\/doi.org\/10.3390\/curroncol29050300","relation":{},"ISSN":["1718-7729"],"issn-type":[{"value":"1718-7729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,20]]}}}