EGFR mutation is an important biomarker in lung cancer patients. Osimertinib, a third-generation EGFR inhibitor, has been proved to have a good therapeutic effect in patients with EGFR mutation. However, the mechanism of resistance to osimertinib remains unclear. In this study, next-generation sequencing of tumor or liquid biopsies after osimertinib resistance was performed. The major resistance mechanisms were EGFR C797S mutation and MET amplification. In addition, fusion mutations of CCDC6-RET gene were found in tissue samples and blood samples of two patients separately. The scientists used a cell line assay to confirm that RET fusion confers resistance to EGFR inhibitor, and the combination of EGFR inhibitor and RET inhibitor, such as BLU-667 or cabozantinib, was an effective treatment strategy in these cell lines. Furthermore, two patients with RET fusion mutation were treated with osimertinib combined with BLU-667. After 8 weeks, the tumors shrank 78%. The results suggest that the combination of osimertinib and BLU-667 can be used to control the osimertinib-resistant lung cancer patients with RET gene fusion.
Source : Piotrowska Z, et al., Cancer Discov, 2018