Yonina R. Murciano-Goroff, Valentina Foglizzo, Jason Chang, Natasha Rekhtman, Ann Elizabeth Sisk, Jamie Gibson, Lia Judka, Kristen Clemens, Paola Roa, Shaza Sayed Ahmed, Nicole V. Bremer, Courtney Lynn Binaco, Sherifah Kemigisha Muzungu, Estelamari Rodriguez, Madeline Merrill, Erica Sgroe, Matteo Repetto, Zsofia K. Stadler, Michael F. Berger, Helena A. Yu, Eneda Toska, Srinivasaraghavan Kannan, Chandra S. Verma, Alexander Drilon, Emiliano Cocco
{"title":"不同MET肿瘤改变对I型和II型MET抑制剂的反应性","authors":"Yonina R. Murciano-Goroff, Valentina Foglizzo, Jason Chang, Natasha Rekhtman, Ann Elizabeth Sisk, Jamie Gibson, Lia Judka, Kristen Clemens, Paola Roa, Shaza Sayed Ahmed, Nicole V. Bremer, Courtney Lynn Binaco, Sherifah Kemigisha Muzungu, Estelamari Rodriguez, Madeline Merrill, Erica Sgroe, Matteo Repetto, Zsofia K. Stadler, Michael F. Berger, Helena A. Yu, Eneda Toska, Srinivasaraghavan Kannan, Chandra S. Verma, Alexander Drilon, Emiliano Cocco","doi":"10.1002/ctm2.70338","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Mutations in c-MET receptor tyrosine kinase (MET) can be primary oncogenic drivers of multiple tumour types or can be acquired as mechanisms of resistance to therapy. MET tyrosine kinase inhibitors (TKIs) are classified as type I or type II inhibitors, with the former binding to the DFG-in, active conformation of MET, and the latter to the DFG-out, inactive conformation of MET. Understanding how the different classes of MET TKIs impact tumours with varied MET alterations is critical to optimising treatment for patients with MET altered cancers. Here, we characterise MET mutations identified in patients’ tumours and assess responsiveness to type I and II TKIs.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We used structural modelling, in vitro kinase and in cell-based assays to assess the response of MET mutations to type I and II TKIs. We then translated our pre-clinical findings and treated patients with MET mutant tumours with selected inhibitors.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>We detected the emergence of four (three previously uncharacterised and one known) MET resistance mutations (MET<sup>G1090A</sup>, MET<sup>D1213H</sup>, MET<sup>R1227K</sup> and a MET<sup>Y1230S</sup>) in samples from patients with multiple solid tumours, including patients who had been previously treated with type I inhibitors.</p>\n \n <p>In silico modelling and biochemical assays across a variety of MET alterations, including the uncharacterised MET<sup>G1090A</sup> and the MET<sup>Y1230S</sup> substitutions, demonstrated impaired binding of type I but not of type II TKIs (i.e., cabozantinib/foretinib). Applying our pre-clinical findings, we then treated two patients (one with a non-small-cell lung cancer and one with a renal cell carcinoma) whose tumours harboured these previously uncharacterised MET alterations with cabozantinib, a type II MET TKI, and observed clinical responses.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Comprehensive characterisation of the sensitivity of mutations to different TKI classes in oncogenic kinases may guide clinical intervention and overcome resistance to targeted therapies in selected cases.</p>\n </section>\n \n <section>\n \n <h3> Key points</h3>\n \n <div>\n <ul>\n \n <li>Kinase mutations in RTKs are primary or secondary drivers in multiple cancer types</li>\n \n <li>Some of these mutations confer resistance to type I but not to type II inhibitors in preclinical samples and in patients</li>\n \n <li>The biochemical characterization of mutations in oncogenic kinases based on their sensitivity to type I and type II inhibitors is crucial to inform clinical intervention</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9000,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70338","citationCount":"0","resultStr":"{\"title\":\"Responsiveness of different MET tumour alterations to type I and type II MET inhibitors\",\"authors\":\"Yonina R. Murciano-Goroff, Valentina Foglizzo, Jason Chang, Natasha Rekhtman, Ann Elizabeth Sisk, Jamie Gibson, Lia Judka, Kristen Clemens, Paola Roa, Shaza Sayed Ahmed, Nicole V. Bremer, Courtney Lynn Binaco, Sherifah Kemigisha Muzungu, Estelamari Rodriguez, Madeline Merrill, Erica Sgroe, Matteo Repetto, Zsofia K. Stadler, Michael F. Berger, Helena A. Yu, Eneda Toska, Srinivasaraghavan Kannan, Chandra S. Verma, Alexander Drilon, Emiliano Cocco\",\"doi\":\"10.1002/ctm2.70338\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Mutations in c-MET receptor tyrosine kinase (MET) can be primary oncogenic drivers of multiple tumour types or can be acquired as mechanisms of resistance to therapy. MET tyrosine kinase inhibitors (TKIs) are classified as type I or type II inhibitors, with the former binding to the DFG-in, active conformation of MET, and the latter to the DFG-out, inactive conformation of MET. Understanding how the different classes of MET TKIs impact tumours with varied MET alterations is critical to optimising treatment for patients with MET altered cancers. Here, we characterise MET mutations identified in patients’ tumours and assess responsiveness to type I and II TKIs.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>We used structural modelling, in vitro kinase and in cell-based assays to assess the response of MET mutations to type I and II TKIs. We then translated our pre-clinical findings and treated patients with MET mutant tumours with selected inhibitors.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>We detected the emergence of four (three previously uncharacterised and one known) MET resistance mutations (MET<sup>G1090A</sup>, MET<sup>D1213H</sup>, MET<sup>R1227K</sup> and a MET<sup>Y1230S</sup>) in samples from patients with multiple solid tumours, including patients who had been previously treated with type I inhibitors.</p>\\n \\n <p>In silico modelling and biochemical assays across a variety of MET alterations, including the uncharacterised MET<sup>G1090A</sup> and the MET<sup>Y1230S</sup> substitutions, demonstrated impaired binding of type I but not of type II TKIs (i.e., cabozantinib/foretinib). Applying our pre-clinical findings, we then treated two patients (one with a non-small-cell lung cancer and one with a renal cell carcinoma) whose tumours harboured these previously uncharacterised MET alterations with cabozantinib, a type II MET TKI, and observed clinical responses.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>Comprehensive characterisation of the sensitivity of mutations to different TKI classes in oncogenic kinases may guide clinical intervention and overcome resistance to targeted therapies in selected cases.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Key points</h3>\\n \\n <div>\\n <ul>\\n \\n <li>Kinase mutations in RTKs are primary or secondary drivers in multiple cancer types</li>\\n \\n <li>Some of these mutations confer resistance to type I but not to type II inhibitors in preclinical samples and in patients</li>\\n \\n <li>The biochemical characterization of mutations in oncogenic kinases based on their sensitivity to type I and type II inhibitors is crucial to inform clinical intervention</li>\\n </ul>\\n </div>\\n </section>\\n </div>\",\"PeriodicalId\":10189,\"journal\":{\"name\":\"Clinical and Translational Medicine\",\"volume\":\"15 5\",\"pages\":\"\"},\"PeriodicalIF\":7.9000,\"publicationDate\":\"2025-05-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70338\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical and Translational Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ctm2.70338\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ctm2.70338","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Responsiveness of different MET tumour alterations to type I and type II MET inhibitors
Background
Mutations in c-MET receptor tyrosine kinase (MET) can be primary oncogenic drivers of multiple tumour types or can be acquired as mechanisms of resistance to therapy. MET tyrosine kinase inhibitors (TKIs) are classified as type I or type II inhibitors, with the former binding to the DFG-in, active conformation of MET, and the latter to the DFG-out, inactive conformation of MET. Understanding how the different classes of MET TKIs impact tumours with varied MET alterations is critical to optimising treatment for patients with MET altered cancers. Here, we characterise MET mutations identified in patients’ tumours and assess responsiveness to type I and II TKIs.
Methods
We used structural modelling, in vitro kinase and in cell-based assays to assess the response of MET mutations to type I and II TKIs. We then translated our pre-clinical findings and treated patients with MET mutant tumours with selected inhibitors.
Results
We detected the emergence of four (three previously uncharacterised and one known) MET resistance mutations (METG1090A, METD1213H, METR1227K and a METY1230S) in samples from patients with multiple solid tumours, including patients who had been previously treated with type I inhibitors.
In silico modelling and biochemical assays across a variety of MET alterations, including the uncharacterised METG1090A and the METY1230S substitutions, demonstrated impaired binding of type I but not of type II TKIs (i.e., cabozantinib/foretinib). Applying our pre-clinical findings, we then treated two patients (one with a non-small-cell lung cancer and one with a renal cell carcinoma) whose tumours harboured these previously uncharacterised MET alterations with cabozantinib, a type II MET TKI, and observed clinical responses.
Conclusions
Comprehensive characterisation of the sensitivity of mutations to different TKI classes in oncogenic kinases may guide clinical intervention and overcome resistance to targeted therapies in selected cases.
Key points
Kinase mutations in RTKs are primary or secondary drivers in multiple cancer types
Some of these mutations confer resistance to type I but not to type II inhibitors in preclinical samples and in patients
The biochemical characterization of mutations in oncogenic kinases based on their sensitivity to type I and type II inhibitors is crucial to inform clinical intervention
期刊介绍：
Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
