Acquired Mechanism of Crizotinib Resistance in NSCLC with MET Exon 14 Skipping

Lung cancer is the most common type of malignant tumor in the world.1Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2018.CA Cancer J Clin. 2018; 68: 7-30Crossref PubMed Scopus (6441) Google Scholar MNNG HOS Transforming gene (MET) exon 14 mutations occur in approximately 4% of lung cancers.2Baldacci S. Kherrouche Z. Descarpentries C. et al.MET exon 14 splicing sites mutations: a new therapeutic opportunity in lung cancer.Rev Mal Respir. 2018; 35: 796-812Google Scholar The efficacy of crizotinib in lung cancer with a MET exon 14 skipping mutation has been demonstrated, but resistance is inevitable.3Suzawa 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: 1248-1260Crossref PubMed Scopus (66) Google Scholar Here we have reported a patient with advanced lung cancer with a MET exon 14 skipping mutation and a MET exon 5 C526F mutation. After the patient progressed through crizotinib treatment, orally administered cabozantinib was effective. The D1246N mutation was found by repeated gene detection; moreover, the exon 14 splice site changed and the exon 5 C526F mutation disappeared (Table 1).Table 1Results of Molecular Diagnostic Assays (Next-Generation Sequencing)Before CrizotinibAfter CrizotinibMET exon 14 splice site (3082–3082+15del16)MET exon 14 splice site (3081–3082+14del)MET exon 5 C526FMET exon 19 D1246NMET, MNNG HOS Transforming gene; del, deletion. Open table in a new tab MET, MNNG HOS Transforming gene; del, deletion. A 83-year-old male smoker presented at the hospital with dry cough. Chest computed tomography (CT) screening revealed a nodule in his right upper lung (Fig. 1A) and multiple enlarged lymph nodes in the right side of his neck and in the supraclavicular and ipsilateral mediastinum. Single-photon emission computed tomography revealed multiple abnormalities in the cervical vertebrae. A diagnosis of adenocarcinoma of the right upper lung was made. Tests for EGFR, ALK receptor tyrosine kinase gene (ALK), and ROS1 were negative. Only one cycle of pemetrexed was administered because of intolerable gastrointestinal toxicity (Fig. 1B). Three months later, the patient had intracranial metastasis (Fig. 1C and Fig. 2A). Next-generation sequencing (NGS) analysis found a MET exon 14 c.3082–3082+15del16 mutation and a C526F mutation in exon 5 of MET in a plasma sample. Crizotinib was administered orally for 6 months until the intracranial lesion had increased in size (Fig. 1D and E and Fig. 2B and C). Crizotinib treatment was continued for another month with concurrent gamma knife radiotherapy to the intracranial lesion. Then, CT revealed that the nodule in the patient's lung had increased in size and pleural effusion had increased (Fig. 1F). Cabozantinib was administered orally in combination with an injection of cisplatin to the chest in place of crizotinib. After 1 month, a portion of the tumor in the lung appeared in the central cavity (Fig. 1G). NGS was performed again on a sample of peripheral blood, revealing an extra D1246N mutation in exon 19 of MET in addition to a different exon 14 c.3081–3082+14del mutation. In this case, we found previously unreported changes in the exon 14 skipping sites in the two NGS results. The patient’s treatment was switched to cabozantinib after D1246N mutation had been found; a large cavity was found in the lung tumor by CT, suggesting that the treatment was effective, which was consistent with previous reports.4Anna L. JinJi Y. XuChao Z. et al.Acquired Y1248H and D1246N mMutations mediate resistance to MET inhibitors in non-small cell lung cancer.Clin Cancer Res. 2017; 23: 4929-4937Google Scholar The exon 5 C526F mutation is a previously unreported mutation that disappeared after oral administration of crizotinib to the patient, suggesting a possible association with type I mesenchymal-endothelial transition tyrosine kinase inhibitor sensitivity. This is the first clinical report of the exon 5 C526F mutation and the first time that there were also changes in the MET exon 14 splice site during treatment with crizotinib. This case can provide a reference for the treatment of similar patients and provide clues for the mechanism of acquired drug resistance to crizotinib. This work was partly supported by the Natural Science Foundation of Anhui Province, People's Republic of China, No.1908085MH260, and Hefei Municipal Independent Innovation Policy “Borrowing and Transferring” Project, People's Republic of China, J2018Y01.