GOPC-ROS1 Rearrangement as an Acquired Resistance Mechanism to Osimertinib and Responding to Crizotinib Combined Treatments in Lung Adenocarcinoma

Tumors invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs), and several studies have demonstrated that EGFR C797S plays key roles in drug resistance.1Jia Y. Yun C.H. Park E. et al.Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors.Nature. 2016; 534: 129-132Crossref PubMed Scopus (501) Google Scholar In our report, we present a case at the first case of golgi-associated PDZ and coiled-coil motif containing gene (GOPC)-ROS1 rearrangement as an acquired resistance mechanism to osimertinib and responding to crizotinib combined treatments with osimertinib in lung adenocarcinoma. A 60-year-old female never-smoker presented to the hospital with symptoms of cough and sputum for 4 months. Thoracic and abdominal computed tomography (CT) scan showed a right middle lobe nodule, multiple lymph node metastases in the right hilar region and mediastinum, and multiple bilateral pulmonary nodules (Fig. 1B). Isotope bone scan and brain magnetic resonance imaging did not show any metastases. A biopsy of the supraclavicular lymph node proved metastatic lung adenocarcinoma. The tumor tissue was identified by amplification refractory mutation system analysis as carrying EGFR exon 19 deletion mutation (Fig. 1A). This patient received orally administered icotinib, 125 mg three times a day, and achieved a partial response (PR) (see Fig. 1B). After 14 months, CT scan showed increased metastasis in the right middle lobe nodule and multiple lymph nodes, multiple bilateral pulmonary nodules, and inflammatory lesions in the right lung (see Fig. 1B). To assess progressive disease, the patient underwent rebiopsy of the supraclavicular lymph node. The pathologic phenotype was lung adenocarcinoma. Molecular detection by next-generation sequencing (NGS) (Burning Rock, Guangzhou, People's Republic of China) showed that EGFR exon19del (EGFR: c2236_2250del, p.Glu_Ala750del) and EGFR exon20 T790M (EGFR: c2369C>T, p.Thr790Met) mutation coexisted (see Fig. 1A). The treatment was changed to osimertinib, 80 mg daily. CT scan showed a decrease in the right middle lobe nodule and multiple bilateral pulmonary nodules after 2 months, and the patient was assessed as having a PR (see Fig. 1B). After 8 months the patient was found to have new bilateral pulmonary nodules and progressive disease, and she underwent bronchial rebiopsy (see Fig. 1B). The pathologic phenotype was still lung adenocarcinoma. Molecular detection by NGS showed EGFR exon19del plus GOPC-ROS1 (G8:R35) rearrangement mutation coexisted (see Fig. 1A). Then the patient received the treatment of crizotinib combined with osimertinib. Two months later, CT scan showed a decrease in bilateral pulmonary nodules, and the patient was evaluated as having a PR (see Fig. 1B). There were no intolerable side effects except grade 2 rash and diarrhea. Tumor evolution was also evaluated (Fig. 1C). In the AURA series studies, EGFR C797S, MNNG HOS Transforming gene (MET) amplification, KRAS mutation, BRAF V600E mutation, and ibroblast growth factor receptor 3 gene (FGFR3) and ret proto-oncogene gene (RET) rearrangement were identified as mechanisms of resistance to osimertinib by NGS.2Ferrara R. Mezquita L. Besse B. Progress in the management of advanced thoracic malignancies in 2017.J Thorac Oncol. 2018; 13: 301-322Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar However, there were no data about the relationship between GOPC-ROS1 rearrangement and osimertinib resistance. And its efficacy to crizotinib was unknown.3Suehara Y. Arcila M. Wang L. et al.Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions.Clin Cancer Res. 2012; 18: 6599-6608Crossref PubMed Scopus (156) Google Scholar In summary, we have presented a case of GOPC-ROS1 rearrangement that was set as a novel acquired resistance mechanism to osimertinib. The combination of crizotinib and osimertinib was proved to be effective and tolerated by this patient. This work was partially supported by the National Natural Science Foundation (NO.81401902 and NO.81501992) and Hunan Natural Science Foundation (2017SK2134). Dr. Zhang prepared the manuscript, Ms. Zeng collected the data, and Mr. Yang modified the manuscript.