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

Abstract

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 (MET^G1090A, MET^D1213H, MET^R1227K and a MET^Y1230S) 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^G1090A and the MET^Y1230S 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.

Keywords

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

References

[1] Bradley CA, Salto-Tellez M, Laurent-Puig P, et al. Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges. Nat Rev Clin Oncol. 2017; 14: 562-576.

[2] Dagogo-Jack I, Yoda S, Lennerz JK, et al. MET alterations are a recurring and actionable resistance mechanism in ALK-positive lung cancer. Clin Cancer Res. 2020; 26: 2535-2545.

[3] Drilon A, Cappuzzo F, Ou SI, et al. Targeting MET in lung cancer: will expectations finally be MET?. J Thorac Oncol. 2017; 12: 15-26.

[4] Guo R, Luo J, Chang J, et al. MET-dependent solid tumours—molecular diagnosis and targeted therapy. Nat Rev Clin Oncol. 2020; 17: 569-587.

[5] Ko J, Jung J, Kim ST, et al. MET gene alterations predict poor survival following chemotherapy in patients with advanced cancer. Pathol Oncol Res. 2022; 28: 1610697.

[6] Recondo G, Che J, Janne PA, et al. Targeting MET dysregulation in cancer. Cancer Discov. 2020; 10: 922-934.

[7] Yao Y, Yang H, Zhu B, et al. Mutations in the MET tyrosine kinase domain and resistance to tyrosine kinase inhibitors in non-small-cell lung cancer. Respir Res. 2023; 24: 28.

[8] Coleman N, Hong L, Zhang J, et al. Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer. ESMO Open. 2021; 6: 100319.

[9] Harada G, Yang S-R, Cocco E, et al. Rare molecular subtypes of lung cancer. Nat Rev Clin Oncol. 2023; 20(4): 229-249.

[10] Hong L, Zhang J, Heymach JV, et al. Current and future treatment options for MET exon 14 skipping alterations in non-small cell lung cancer. Ther Adv Med Oncol. 2021; 13: 1758835921992976.

[11] Peschard P, Fournier TM, Lamorte L, et al. Mutation of the c-Cbl TKB domain binding site on the MET receptor tyrosine kinase converts it into a transforming protein. Mol Cell. 2001; 8: 995-1004.

[12] Suzawa K, Offin M, Schoenfeld AJ, et al. Acquired MET exon 14 alteration drives secondary resistance to epidermal growth factor receptor tyrosine kinase inhibitor in EGFR-mutated lung cancer. JCO Precis Oncol. 2019; 3: PO.19.00011.

[13] Berthou S, Aebersold DM, Schmidt LS, et al. The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants. Oncogene. 2004; 23: 5387-5393.

[14] Davies KD, Ng TL, Estrada-Bernal A, et al. Dramatic response to crizotinib in a patient with lung cancer positive for an HLA-DRB1-MET gene fusion. JCO Precis Oncol. 2017: 2017: PO.17.00117.

[15] Frigault MM, Signoretti S, Markovets A, et al. Abstract 4541: MET gene copy number gains evaluated by NGS is more predictive than other methods to enrich for papillary RCC patients sensitive to savolitinib, a selective MET inhibitor. Cancer Res. 2018; 78: 4541-4541.

[16] Lu S, Fang J, Cao L, et al. Abstract CT031: preliminary efficacy and safety results of savolitinib treating patients with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations. Cancer Res. 2019; 79: CT031-CT031.

[17] Vojnic M, Odintsov I, Liu Z, et al. 2295P pan-cancer prevalence of MET fusions and clinical response to MET-targeted therapy. Ann Oncol. 2023; 34: S1175.

[18] Drilon A, Clark JW, Weiss J, et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat Med. 2020; 26: 47-51.

[19] Landi L, Chiari R, Tiseo M, et al. Crizotinib in MET-deregulated or ROS1-rearranged pretreated non-small cell lung cancer (METROS): a phase II, prospective, multicenter, two-arms trial. Clin Cancer Res. 2019; 25: 7312-7319.

[20] Paik PK, Veillon R, Cortot AB, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations. J Clin Oncol. 2019; 37: 9005-9005.

[21] Wolf J, Seto T, Han J-Y, et al. Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): efficacy data from the phase II GEOMETRY mono-1 study. J Clin Oncol. 2019; 37: 9004-9004.

[22] Wolf J, Seto T, Han JY, et al. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J Med. 2020; 383: 944-957.

[23] Paik PK, Felip E, Veillon R, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 2020; 383: 931-943.

[24] Fujino T, Kobayashi Y, Suda K, et al. Sensitivity and resistance of MET exon 14 mutations in lung cancer to eight MET tyrosine kinase inhibitors in vitro. J Thorac Oncol. 2019; 14: 1753-1765.

[25] Roskoski R. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol Res. 2016; 103: 26-48.

[26] Xia Y, Jin R, Li M, et al. Potent antitumor activity of ensartinib in MET exon 14 skipping-mutated non-small cell lung cancer. Cancer Lett. 2023; 561: 216140.

[27] Engstrom LD, Aranda R, Lee M, et al. Glesatinib exhibits antitumor activity in lung cancer models and patients harboring MET exon 14 mutations and overcomes mutation-mediated resistance to type I MET inhibitors in nonclinical models. Clin Cancer Res. 2017; 23: 6661-6672.

[28] Tiedt R, Degenkolbe E, Furet P, et al. A drug resistance screen using a selective MET inhibitor reveals a spectrum of mutations that partially overlap with activating mutations found in cancer patients. Cancer Res. 2011; 71: 5255-5264.

[29] Recondo G, Bahcall M, Spurr LF, et al. Molecular mechanisms of acquired resistance to MET tyrosine kinase inhibitors in patients with MET exon 14-mutant NSCLC. Clin Cancer Res. 2020; 26: 2615-2625.

[30] Vojnic M, Kubota D, Kurzatkowski C, et al. Acquired BRAF rearrangements induce secondary resistance to EGFR therapy in EGFR-mutated lung cancers. J Thorac Oncol. 2019; 14: 802-815.

[31] Bahcall M, Sim T, Paweletz CP, et al. Acquired METD1228V mutation and resistance to MET inhibition in lung cancer. Cancer Discov. 2016; 6: 1334-1341.

[32] Heist RS, Sequist LV, Borger D, et al. Acquired resistance to crizotinib in NSCLC with MET exon 14 skipping. J Thorac Oncol. 2016; 11: 1242-1245.

[33] Pecci F, Nakazawa S, Ricciuti B, et al. Activating point mutations in the MET kinase domain represent a unique molecular subset of lung cancer and other malignancies targetable with MET inhibitors. Cancer Discov. 2024; 14: 1440-1456.

[34] Cheng DT, Mitchell TN, Zehir A, et al. Memorial Sloan Kettering-integrated mutation profiling of actionable cancer targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn. 2015; 17: 251-264. JMD.

[35] Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017; 23: 703-713.

[36] Benayed R, Offin M, Mullaney K, et al. High yield of RNA sequencing for targetable kinase fusions in lung adenocarcinomas with no mitogenic driver alteration detected by DNA sequencing and low tumor mutation burden. Clin Cancer Res. 2019; 25: 4712-4722.

[37] Zheng Z, Liebers M, Zhelyazkova B, et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med. 2014; 20: 1479-1484.

[38] Brannon AR, Jayakumaran G, Diosdado M, et al. Enhanced specificity of high sensitivity somatic variant profiling in cell-free DNA via paired normal sequencing: design, validation, and clinical experience of the MSK-ACCESS liquid biopsy assay. bioRxiv. 2020; 175471: 20200627.

[39] Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012; 2: 401-404.

[40] Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013; 6: pl1-pl1.

[41] Guo R, Berry LD, Aisner DL, et al. MET IHC is a poor screen for MET amplification or MET exon 14 mutations in lung adenocarcinomas: data from a tri-institutional cohort of the lung cancer mutation consortium. J Thorac Oncol. 2019; 14: 1666-1671.

[42] Sholl LM, Aisner DL, Varella-Garcia M, et al. Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: the lung cancer mutation consortium experience. J Thorac Oncol. 2015; 10: 768-777.

[43] Lee TS, Allen BK, Giese TJ, et al. Alchemical binding free energy calculations in AMBER20: advances and best practices for drug discovery. J Chem Inf Model. 2020; 60: 5595-5623.

[44] Maier JA, Martinez C, Kasavajhala K, et al. ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB. J Chem Theory Comput. 2015; 11: 3696-3713.

[45] Wang J, Wolf RM, Caldwell JW, et al. Development and testing of a general Amber force field. J Comput Chem. 2004; 25: 1157-1174.

[46] Kannan S, Poulsen A, Yang HY, et al. Probing the binding mechanism of MNK inhibitors by docking and molecular dynamics simulations. Biochemistry. 2015; 54: 32-46.

[47] Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graphics. 1996; 14: 33-38.

[48] DeLano WLJCNPC. Pymol: an open-source molecular graphics tool. CCP4 Newsl Protein Crystallogr. 2002; 40: 82-92.

[49] Kannan S, Tan DS, Verma CS. Effects of single nucleotide polymorphisms on the binding of afatinib to EGFR: a potential patient stratification factor revealed by modeling studies. J Chem Inf Model. 2019; 59: 309-315.

[50] Cocco E, Schram AM, Kulick A, et al. Resistance to TRK inhibition mediated by convergent MAPK pathway activation. Nat Med. 2019; 25: 1422-1427.

[51] Cai B, Li X, Huang X, et al. Case report: sequential combination targeted therapy with type I and II MET inhibitors in a metastatic EGFR-mutated, MET-amplified NSCLC patient with acquired MET Y1230H mutation. Front Oncol. 2021; 11: 738832.

[52] Febres-Aldana CA, Vojnic M, Odintsov I, et al. Pan-cancer analysis of oncogenic MET fusions reveals distinct pathogenomic subsets with differential sensitivity to MET-targeted therapy. Cancer Discov. 2025. Online ahead of print. https://doi.org/10.1158/2159-8290.CD-24-0417

[53] Guo R, Offin M, Brannon AR, et al. MET exon 14-altered lung cancers and MET inhibitor resistance. Clin Cancer Res. 2021; 27: 799-806.

[54] Nisa L, Häfliger P, Poliaková M, et al. PIK3CA hotspot mutations differentially impact responses to MET targeting in MET-driven and non-driven preclinical cancer models. Mol Cancer. 2017; 16: 93.

[55] McDermott U, Pusapati RV, Christensen JG, et al. Acquired resistance of non-small cell lung cancer cells to MET kinase inhibition is mediated by a switch to epidermal growth factor receptor dependency. Cancer Res. 2010; 70: 1625-1634.

[56] Bahcall M, Awad MM, Sholl LM, et al. Amplification of wild-type KRAS imparts resistance to crizotinib in MET exon 14 mutant non-small cell lung cancer. Clin Cancer Res. 2018; 24: 5963-5976.

[57] Suzawa K, Offin M, Lu D, et al. Activation of KRAS mediates resistance to targeted therapy in MET exon 14-mutant non-small cell lung cancer. Clin Cancer Res. 2019; 25: 1248-1260.

[58] Ou SI, Young L, Schrock AB, et al. Emergence of preexisting MET Y1230C mutation as a resistance mechanism to crizotinib in NSCLC with MET exon 14 skipping. J Thorac Oncol. 2017; 12: 137-140.

[59] Qi J, McTigue MA, Rogers A, et al. Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors. Cancer Res. 2011; 71: 1081-1091.

[60] Cocco E, Lee JE, Kannan S, et al. TRK xDFG mutations trigger a sensitivity switch from type I to II kinase inhibitors. Cancer Discov. 2021; 11: 126-141.

[61] Drilon A, Nagasubramanian R, Blake JF, et al. A next-generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK fusion-positive solid tumors. Cancer Discov. 2017; 7: 963-972.

[62] Brown BP, Zhang YK, Westover D, et al. On-target resistance to the mutant-selective EGFR inhibitor osimertinib can develop in an allele-specific manner dependent on the original EGFR-activating mutation. Clin Cancer Res. 2019; 25: 3341-3351.

[63] Drilon A, Rekhtman N, Arcila M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol. 2016; 17: 1653-1660.

[64] Nakaoku T, Kohno T, Araki M, et al. A secondary RET mutation in the activation loop conferring resistance to vandetanib. Nat Commun. 2018; 9: 625.

[65] Laine E, Auclair C, Tchertanov L. Allosteric communication across the native and mutated KIT receptor tyrosine kinase. PLoS Comput Biol. 2012; 8: e1002661.

[66] Iaxx R, Lefort F, Domblides C, et al. An evaluation of cabozantinib for the treatment of renal cell carcinoma: focus on patient selection and perspectives. Ther Clin Risk Manag. 2022; 18: 619-632.

[67] Schmidinger M, Danesi R. Management of adverse events associated with cabozantinib therapy in renal cell carcinoma. Oncologist. 2018; 23: 306-315.

[68] Drilon A, Somwar R, Wagner JP, et al. A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer. Clin Cancer Res. 2016; 22: 2351-2358.

[69] Fujino T, Suda K, Koga T, et al. Foretinib can overcome common on-target resistance mutations after capmatinib/tepotinib treatment in NSCLCs with MET exon 14 skipping mutation. J Hematol Oncol. 2022; 15: 79.

[70] Pan Y, Deng C, Qiu Z, et al. The resistance mechanisms and treatment strategies for ALK-rearranged non-small cell lung cancer. Front Oncol. 2021; 11: 713530.

[71] Riedel R, Fassunke J, Tumbrink HL, et al. Resistance to MET inhibition in MET-dependent NSCLC and therapeutic activity after switching from type I to type II MET inhibitors. Eur J Cancer. 2023; 179: 124-135.

RIGHTS & PERMISSIONS

2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.