Murciano-Goroff Yonina R, Foglizzo Valentina, Chang Jason, Rekhtman Natasha, Sisk Ann Elizabeth, Gibson Jamie, Judka Lia, Clemens Kristen, Roa Paola, Ahmed Shaza Sayed, Bremer Nicole V, Binaco Courtney Lynn, Muzungu Sherifah Kemigisha, Rodriguez Estelamari, Merrill Madeline, Sgroe Erica, Repetto Matteo, Stadler Zsofia K, Berger Michael F, Yu Helena A, Toska Eneda, Kannan Srinivasaraghavan, Verma Chandra S, Drilon Alexander, Cocco Emiliano
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida, USA.
Clin Transl Med. 2025 May;15(5):e70338. doi: 10.1002/ctm2.70338.
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.
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.
We detected the emergence of four (three previously uncharacterised and one known) MET resistance mutations (MET, MET, MET and a MET) 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 MET and the MET 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.
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.
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.
c-MET受体酪氨酸激酶（MET）突变可能是多种肿瘤类型的原发性致癌驱动因素，也可能是作为对治疗产生耐药性的机制而获得的。MET酪氨酸激酶抑制剂（TKIs）分为I型或II型抑制剂，前者与MET的DFG-in活性构象结合，后者与MET的DFG-out非活性构象结合。了解不同类别的MET TKIs如何影响具有不同MET改变的肿瘤对于优化MET改变癌症患者的治疗至关重要。在此，我们对患者肿瘤中鉴定出的MET突变进行了表征，并评估了对I型和II型TKIs的反应性。
我们使用结构建模、体外激酶和基于细胞的试验来评估MET突变对I型和II型TKIs的反应。然后，我们将临床前研究结果转化应用于用选定抑制剂治疗MET突变肿瘤患者。
我们在多种实体瘤患者的样本中检测到四个（三个先前未表征的和一个已知的）MET耐药突变（MET、MET、MET和一个MET），包括先前接受过I型抑制剂治疗的患者。在多种MET改变（包括未表征的MET和MET替代）的计算机模拟和生化试验中，结果表明I型TKIs（而非II型TKIs，即卡博替尼/福瑞替尼）的结合受损。应用我们的临床前研究结果，我们随后用II型MET TKI卡博替尼治疗了两名患者（一名患有非小细胞肺癌，一名患有肾细胞癌），其肿瘤具有这些先前未表征的MET改变，并观察到了临床反应。
对致癌激酶中突变对不同TKI类别的敏感性进行全面表征可能指导临床干预，并在某些情况下克服对靶向治疗的耐药性。
RTK中的激酶突变是多种癌症类型的原发性或继发性驱动因素
在临床前样本和患者中，其中一些突变对I型抑制剂产生耐药性，但对II型抑制剂不产生耐药性
基于致癌激酶突变对I型和II型抑制剂的敏感性进行生化表征对于指导临床干预至关重要。
