Drug Repurposing Applications to Overcome Male Predominance via Targeting G2/M Checkpoint in Human Esophageal Squamous Cell Carcinoma

SIMPLE SUMMARY: Sex biases in cancer incidence and cancer mortality exist in the majority of cancer types. Esophageal squamous cell carcinoma (ESCC) is a typical malignancy with higher mortality rates and worse responses to treatment in males versus females. To overcome the male predominance in ESCC, more therapeutic targets need to be identified. Meanwhile, age is also an important contributor that should be included when we consider sex bias in cancer. In this study, we used multi-omics data from 663 ESCC patients and found that G2/M checkpoint pathway-related sex bias and age bias were significantly present in genomics, transcriptomics, and epigenomics. Our findings suggest that G2/M targets may be included in combination therapy for male patients to improve the efficacy of ESCC treatment. ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is strongly characterized by a male predominance with higher mortality rates and worse responses to treatment in males versus females. Despite the role of sex hormones, other causes that may contribute to sex bias in ESCC remain largely unknown, especially as age increases and the hormone difference begins to diminish between sexes. In this study, we analyzed genomics, transcriptomics, and epigenomics from 663 ESCC patients and found that G2/M checkpoint pathway-related sex bias and age bias were significantly present in multi-omics data. In accordance with gene expression patterns across sexes, ten compounds were identified by applying drug repurposing from three drug sensitivity databases: The Connective Map (CMap), Genomics of Drug Sensitivity in Cancer (GDSC), and The Cancer Therapeutic Response Portal (CTRP). MK1775 and decitabine showed better efficacy in two male ESCC cell lines in vitro and in vivo. The drugs’ relevance to the transition between G2 and M was especially evident in male cell lines. In our study, we first validated the sex bias of the G2/M checkpoint pathway in ESCC and then determined that G2/M targets may be included in combination therapy for male patients to improve the efficacy of ESCC treatment.