MET Mutation Is a Potential Therapeutic Target for Advanced Endometrial Cancer

SIMPLE SUMMARY: Endometrial cancer is the most common gynecological cancer in developed countries. At initial diagnosis, extra-uterine spread is observed in about 25% of patients. Chemotherapy is the suggested mode of treatment for patients with extra-uterine metastasis; however, the 5-year overall survival rate of these patients remains poor. The development of new therapeutic strategies to improve the poor clinical outcome of patients with advanced endometrial cancer is still in great demand. In this study, we aim to understand the genomic landscape of advanced endometrial cancer and identify new therapeutic targets. Integrated genomic, pathological, and clinical data are analyzed to identify the survival-associated genomic alterations. In addition, the impacts of the genomic alterations are examined in silico, in vitro, and in vivo. The results of this study may aid in developing biomarker-guided treatments for patients with advanced endometrial cancer. ABSTRACT: An optimal therapeutic regimen for endometrial cancer with extra-uterine metastasis is unavailable. This study aims to improve our understanding of the genomic landscape of advanced endometrial cancer and identify potential therapeutic targets. The clinical and genomic profiles of 81 patients with stage III or IV endometrial cancer were integrated. To identify genomic aberrations associated with clinical outcomes, Cox proportional hazard regression was used. The impacts of the genomic aberrations were validated in vitro and in vivo. The mutation status of MET, U2AF1, BCL9, PPP2R1A, IDH2, CBL, BTK, and CHEK2 were positively correlated with poor clinical outcomes. MET mutations occurred in 30% of the patients who presented with poor overall survival (hazard ratio, 2.606; 95% confidence interval, 1.167~5.819; adjusted p-value, 0.067). Concurrent MET and KRAS mutations presented with the worst outcomes. MET mutations in hepatocyte growth factor (HGF)-binding (58.1%) or kinase (16.2%) domains resulted in differential HGF-induced c-MET phosphorylation. Different types of MET mutations differentially affected tumor growth and displayed different sensitivities to cisplatin and tyrosine kinase inhibitors. MET N375S mutation is a germline variant that causes chemoresistance to cisplatin, with a high incidence in Eastern Asia. This study highlights the ethnic differences in the biology of the disease, which can influence treatment recommendations and the genome-guided clinical trials of advanced endometrial cancer.