Journal of Thoracic Oncology最新文献

{"title":"Activating mutations in the MET kinase domain co-occur with other driver oncogenes and mediate resistance to targeted therapy in NSCLC.","authors":"Seshiru Nakazawa, Federica Pecci, Biagio Ricciuti, Felix H Gottlieb, Francesco Facchinetti, Guilherme Harada, Monica F Chen, Matteo Repetto, Flavia Giacomini, Jie Jiang, Marie-Anaïs Locquet, Maisam Makarem, Joao V Alessi, Alessandro Di Federico, Mihaela Aldea, Edoardo Garbo, Malini M Gandhi, Arushi Saini, Danielle Haradon, Magda Bahcall, William W Feng, Jessica K Lee, Alexa B Schrock, Alexander Drilon, Mark M Awad, Pasi A Jänne","doi":"10.1016/j.jtho.2025.03.045","DOIUrl":"https://doi.org/10.1016/j.jtho.2025.03.045","url":null,"abstract":"<p><strong>Introduction: </strong>MET tyrosine kinase domain (TKD) mutations have recently been characterized as de novo oncogenic drivers in non-small cell lung cancer (NSCLC). However, whether activating MET TKD mutations can confer resistance to targeted therapy in non-MET, oncogene-driven NSCLCs remains unclear.</p><p><strong>Material and methods: </strong>To characterize the genomic features of tumors with MET TKD mutations in oncogene-driven NSCLC, we performed tumor genomic profiling on two different cohorts of patients with NSCLC. Preclinical models of the most frequently observed MET TKD mutations were generated to determine the effect on sensitivity to targeted therapy. Treatment strategies to overcome MET TKD mutation-mediated resistance were further explored.</p><p><strong>Results: </strong>Genomic profiling from >115,000 patients with NSCLC demonstrated that activating MET TKD mutations are prevalent in 0.15% of cases, and that about half of them co-occur with another oncogenic driver, with a differential pattern in co-occurring MET TKD mutations according to the oncogenic alteration. A review of eight cases with sequential genomic testing revealed that MET TKD mutation was acquired after systemic therapy in 88% of cases, with a potential contribution of APOBEC mutagenesis underlying this process. In vitro, MET TKD mutation conferred resistance to targeted therapy in diverse oncogene-driven models, which could be overcome by combinatorial treatment against both the primary oncogene and the MET TKD mutation.</p><p><strong>Conclusions: </strong>MET TKD mutation can act as an off-target mechanism of resistance in diverse oncogene-driven NSCLC. Combination therapy with an effective MET-targeted therapy can potentially overcome MET TKD mutation-mediated resistance.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PP01.06 Aurora Kinase A Inhibition Potentiates KRASG12C Inhibition and Overcomes Resistance to Sotorasib in Lung Cancer","authors":"Jong Woo Lee,&nbsp;Jackie Shi,&nbsp;Julian Barrantes,&nbsp;Sundong Kim,&nbsp;Sebastian Cruz-Gomez,&nbsp;Cindy Yang,&nbsp;Barbara Burtness","doi":"10.1016/j.jtho.2025.03.014","DOIUrl":"10.1016/j.jtho.2025.03.014","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 4","pages":"Page S5"},"PeriodicalIF":21.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OA05.01 Deep Mutational Scanning Reveals Novel EGFR Mutations Conferring Resistance to Osimertinib and BLU-945","authors":"Dylan Yueyang Wang ,&nbsp;Michela Ranieri ,&nbsp;Fiona Sherman ,&nbsp;Jiehui Deng ,&nbsp;Kwok-Kin Wong ,&nbsp;Elaine Shum ,&nbsp;John T. Poirier","doi":"10.1016/j.jtho.2025.03.007","DOIUrl":"10.1016/j.jtho.2025.03.007","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 4","pages":"Page S2"},"PeriodicalIF":21.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PP01.14 Paired Sample Analyses of NSCLC After SCLC Transformation","authors":"Brinda Gupta ,&nbsp;Kieran Sweeney ,&nbsp;Andrew Elliott ,&nbsp;Jennifer Marks ,&nbsp;Ari Vanderwalde ,&nbsp;Sonam Puri ,&nbsp;Misty D. Shields ,&nbsp;Jorge J. Nieva ,&nbsp;Heloisa P. Soares ,&nbsp;Patrick C. Ma ,&nbsp;Balazs Halmos ,&nbsp;Stephen V. Liu","doi":"10.1016/j.jtho.2025.03.021","DOIUrl":"10.1016/j.jtho.2025.03.021","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 4","pages":"Page S8"},"PeriodicalIF":21.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PP01.04 Targeting the Minimal Residual Disease to Increase the Targeted Therapy Depth of Response in EGFR-Driven Lung Cancer","authors":"David Bracquemond ,&nbsp;Maicol Mancini ,&nbsp;Antonio Maraver","doi":"10.1016/j.jtho.2025.03.012","DOIUrl":"10.1016/j.jtho.2025.03.012","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 4","pages":"Page S4"},"PeriodicalIF":21.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex and Common Germline Variants Affect the Toxicity Profile and Pharmacokinetics of Alectinib: A Nationwide Cohort Study in Patients With ALK-Positive NSCLC","authors":"Niels Heersche MD ,&nbsp;Daan A.C. Lanser MD ,&nbsp;M. Benthe Muntinghe-Wagenaar MD ,&nbsp;Ma Ida Mohmaed Ali PharmD ,&nbsp;Ezgi B. Ulas BSc ,&nbsp;Tessa M.A. Trooster BSc ,&nbsp;Evert de Jonge BSc ,&nbsp;Esther Oomen-de Hoop PhD ,&nbsp;Marthe S. Paats MD, PhD ,&nbsp;Idris Bahce MD, PhD ,&nbsp;Sander Croes PhD ,&nbsp;Lizza E.L. Hendriks MD, PhD ,&nbsp;Anthonie J. van der Wekken MD, PhD ,&nbsp;Anne-Marie C. Dingemans MD, PhD ,&nbsp;Alwin D.R. Huitema PhD ,&nbsp;Ron H.N. van Schaik PhD ,&nbsp;Ron H.J. Mathijssen MD, PhD ,&nbsp;G.D. Marijn Veerman MD, PhD","doi":"10.1016/j.jtho.2024.11.025","DOIUrl":"10.1016/j.jtho.2024.11.025","url":null,"abstract":"<div><h3>Introduction</h3><div>Alectinib, a small-molecule kinase inhibitor, is used as first-line treatment for ALK-positive (<em>ALK</em>+) NSCLC. Albeit generally well-tolerated, a considerable subset of patients requires dose adjustments due to drug-related toxicity. Single-nucleotide polymorphisms in genes related to the metabolism of alectinib may upfront identify patients at risk for toxicity.</div></div><div><h3>Methods</h3><div>In this multicenter observational cohort study in patients with advanced <em>ALK</em>+ NSCLC receiving alectinib treatment, we investigated the association between toxicity, pharmacokinetics, and key genetic variants in <em>ABCB1</em>, <em>CYP3A4</em>, <em>PPAR-α</em>, <em>POR</em>, and <em>CYP3A5</em>. Data on demographics, adverse events, and alectinib trough levels were collected from five hospitals.</div></div><div><h3>Results</h3><div>Among 215 patients, 47% experienced severe toxicity. Women experienced more severe toxicity (female versus male: 56% versus 34%; <em>p</em> = 0.001) and had +35% higher alectinib trough levels (<em>p</em> &lt; 0.001). Homozygous carriers of the <em>PPAR-α</em> 209G&gt;A variant exhibited a higher incidence of grade greater than or equal to 3 toxicity (38%) compared with patients who carried at least one wild-type allele (11%) (<em>p</em> = 0.004). This remained significant after Bonferroni correction. Patients who experienced severe toxicity had +18.5% (95% confidence interval: 2.9%–36.6%; <em>p</em> = 0.019) higher trough levels.</div></div><div><h3>Conclusions</h3><div>Female patients encounter more severe toxicity due to higher alectinib exposure, which warrants further exploration. <em>PPAR-α</em> 209G&gt;A significantly increased relevant alectinib-induced toxicity, most likely due to an increase in alectinib exposure. Pretreatment testing for genetic variants with a subsequent dose reduction could provide a viable approach to reduce alectinib-related toxicity.</div></div>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 4","pages":"Pages 475-486"},"PeriodicalIF":21.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PP01.26 Investigating for Blood Circulating N-Linked Glycoproteins Associated With Immunotherapy Response in Pleural Mesothelioma","authors":"Pierre Marchal ,&nbsp;Joel Spies ,&nbsp;Sophie Braga Lagache ,&nbsp;Lydie Lane ,&nbsp;Manfred Heller ,&nbsp;Ferdinando Cerciello","doi":"10.1016/j.jtho.2025.03.029","DOIUrl":"10.1016/j.jtho.2025.03.029","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 4","pages":"Page S11"},"PeriodicalIF":21.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OA02.01 Selective Translation of PBK (PDZ-Binding Kinase) is a Novel Mechanism of Drug Tolerance to Targeted Therapies in EGFR-Mutant Lung Cancer","authors":"Camille Léonce ,&nbsp;Anne-Laure Desage ,&nbsp;Nour El-Houda Mourksi ,&nbsp;Geneviève De Souza ,&nbsp;Béatrice Vanbervliet ,&nbsp;Camille Charrondière ,&nbsp;Constance Nicq ,&nbsp;Aurélie Swalduz ,&nbsp;Gabriel Ichim ,&nbsp;Jean-Jacques Diaz ,&nbsp;Christine Lovly ,&nbsp;Julien Mazières ,&nbsp;Mayeul Tabutin ,&nbsp;Maurice Pérol ,&nbsp;Sylvie Lantuejoul ,&nbsp;Olivier Calvayrac ,&nbsp;Fabien Forest ,&nbsp;Virginie Marcel ,&nbsp;Pierre Saintigny ,&nbsp;Sandra Ortiz- Cuaran","doi":"10.1016/j.jtho.2025.03.005","DOIUrl":"10.1016/j.jtho.2025.03.005","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 4","pages":"Page S1"},"PeriodicalIF":21.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PP01.01 Oncogenic Signaling is Rewired to Support Nucleotide Metabolism in Acquired Resistance to Targeted Therapies in NSCLC","authors":"Jaime L. Schneider ,&nbsp;Yutong Dai ,&nbsp;Ishita Dhiman ,&nbsp;Jingpeng Chen ,&nbsp;Shakchhi Joshi ,&nbsp;Kiran Kurmi ,&nbsp;Morgan Payne ,&nbsp;Brandon Gassaway ,&nbsp;Steven Gygi ,&nbsp;Jessica J. Lin ,&nbsp;Aaron Hata ,&nbsp;Marcia Haigis","doi":"10.1016/j.jtho.2025.03.009","DOIUrl":"10.1016/j.jtho.2025.03.009","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 4","pages":"Page S3"},"PeriodicalIF":21.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PP01.16 Ixazomib Overcomes Platinum Resistance and Induces Autophagy-Mediated Cell Death in Lung Adenocarcinoma","authors":"Muthamil Iniyan Appadurai ,&nbsp;Zahraa Wajih Alsafwani ,&nbsp;Sanjib Chaudhary ,&nbsp;Ashu Shah ,&nbsp;Pranay Somavarapu ,&nbsp;Sriman N. Dooshety ,&nbsp;Ben S. Kubicek ,&nbsp;Surinder K. Batra ,&nbsp;Imayavaramban Lakshmanan ,&nbsp;Apar Kishor Ganti","doi":"10.1016/j.jtho.2025.03.023","DOIUrl":"10.1016/j.jtho.2025.03.023","url":null,"abstract":"","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"20 4","pages":"Page S9"},"PeriodicalIF":21.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}