Molecular subtyping of endometrial carcinoma cell lines uncovers subtype-specific targetable vulnerabilities

Endometrial carcinoma (EC), the most common gynecologic cancer type, encompasses multiple molecular subtypes that have consistent prognostic values and are being adopted in clinical practice to guide treatment decisions. However, it remains unclear whether each of these molecular subtypes have unique therapeutic vulnerabilities that can be exploited for advancing the management of ECs. Through analyzing the genomic features of a panel of 39 EC cell lines, we identified multiple tumor cell lines representing each molecular subtype. Histologic and immunochemical analyses of xenografted tumors from these cell lines confirmed their resemblance of cognate primary EC molecular subtypes, both by histology and the protein expression status of mismatch repair genes, p53 and SWI/SNF members in corresponding subtypes. Further investigation of the publicly available genome-wide CRISPR data for EC cell lines identified multiple specific genetic vulnerabilities in mismatch repair-deficient, p53-abnormal and ARID1A and ARID1B-dual deficient EC cell lines, respectively. Particularly, ARID1A and ARID1B-dual deficient EC cells selectively rely on mitochondria oxidative phosphorylation in vitro and in vivo . Therefore, our study demonstrates the utility of EC cell line models for uncovering and validating therapeutic vulnerabilities of each EC molecular subtype.