Responsiveness of different MET tumour alterations to type I and type II MET inhibitors

Responsiveness of different MET tumour alterations to type I and type II MET inhibitors

Clinical and Translational Medicine

10.1002/ctm2.70338

https://doi.org/10.1002/ctm2.70338

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

MET, resistance to targeted therapy, type I and type II TKIs

29 May 2025

Murciano‐Goroff, Y. R., Foglizzo, V., Chang, J., Rekhtman, N., Sisk, A. E., Gibson, J., Judka, L., Clemens, K., Roa, P., Ahmed, S. S., Bremer, N. V., Binaco, C. L., Muzungu, S. K., Rodriguez, E., Merrill, M., Sgroe, E., Repetto, M., Stadler, Z. K., Berger, M. F., … Cocco, E. (2025). Responsiveness of different MET tumour alterations to type I and type II MET inhibitors. Clinical and Translational Medicine, 15(5). Portico. https://doi.org/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.MethodsWe 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.ResultsWe 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.ConclusionsComprehensive 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

Attribution 4.0 International (CC BY 4.0)

This research is supported by core funding from: A*STAR - Bioinformatics Institute
Grant Reference no. : NA

This is the peer reviewed version of the following article: Murciano‐Goroff, Y. R., Foglizzo, V., Chang, J., Rekhtman, N., Sisk, A. E., Gibson, J., Judka, L., Clemens, K., Roa, P., Ahmed, S. S., Bremer, N. V., Binaco, C. L., Muzungu, S. K., Rodriguez, E., Merrill, M., Sgroe, E., Repetto, M., Stadler, Z. K., Berger, M. F., … Cocco, E. (2025). Responsiveness of different MET tumour alterations to type I and type II MET inhibitors. Clinical and Translational Medicine, 15(5). Portico. https://doi.org/10.1002/ctm2.70338 , which has been published in final form at https://doi.org/10.1002/ctm2.70338. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.

https://oar.a-star.edu.sg/communities-collections/articles/22427

2001-1326
2001-1326

Bioinformatics Institute

https://doi.org/10.1002/ctm2.70338