Abstract
Abstract
Purpose: MET fusions are oncogenic drivers of multiple cancers including non-small cell lung cancer (NSCLC). While MET fusion-positive tumors can be sensitive to MET tyrosine kinase inhibitors (TKI), to date no mechanisms of TKI resistance have been identified or characterized for MET fusion-positive disease.
Experimental Design: Serial targeted genomic sequencing (MSK-IMPACT) was performed in clinical samples from a MET fusion-positive NSCLC treated with the type Ia MET TKI crizotinib. Structural modeling and in vitro kinase assays were used to characterize crizotinib resistance and to test the activity of MET inhibitors with alternative binding modes.
Results: A novel MET G1090A resistance mutation was identified in a patient with a CD47-MET-rearranged NSCLC after crizotinib progression. In silico structural modeling and simulations indicated that the 2,6-dichloro-3-fluorophenyl moiety present on crizotinib directly binds to the side chain of the Y1230 residue in the activation loop of the MET wild type (WT) kinase. In the MET G1090A mutant kinase, the position of the Y1230 residue is predicted to be flipped roughly 180°. As a result, the interaction between crizotinib and Y1230 is compromised; this in turn is predicted to reduce crizotinib’s binding affinity for the mutant kinase. Similar results were obtained when MET WT and G1090A mutant kinases were modeled in complex with selective type Ib MET TKI (i.e., capmatinib, savolitinib and tepotinib). Conversely, we found that type II agents (i.e., cabozantinib and foretinib) were not predicted to interact with Y1230. Therefore, their binding affinity to the mutant MET kinase was predicted to be retained. In vitro kinase assays performed using titrations of crizotinib and capmatinib (representative type I agents) and of cabozantinib (representative type II agent) showed that all three TKI were active against the MET WT kinase (calculated IC50 of 2.5nM, 3.89nM and 1.59nM, respectively). However, the calculated IC50 for crizotinib and capmatinib were 6.04- and 48.4-fold higher than the calculated IC50 for cabozantinib against the MET G1090A mutant kinase. Consistent with the prediction of type II inhibitor activity, the patient was transitioned to cabozantinib. A marked clinical, radiographic, and metabolic response was observed.
Conclusions: In MET fusion-positive cancers, the novel MET G1090A resistance mutation drives resistance to type I MET kinase inhibition. Drug binding mode switching to type II MET inhibition overcomes preclinical and clinical resistance, highlighting the need for further rational type II inhibitor development.
Citation Format: Yonina R. Murciano-Goroff, Srinivasaraghavan Kannan, Jason C. Chang, Ryma Benayed, Ilya Blokhin, Natasha Rekhtman, Ann Elizabeth Sisk, Jaime Gibson, Lia Judka, Lauren Kaplanis, Madeline Merrill, Erica Sgroe, Chandra S. Verma, Alexander Drilon, Emiliano Cocco. Switching inhibitor class overcomes crizotinib resistance in a MET fusion-positive NSCLC with a novel acquired MET G1090A mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5239.