Endometrial cancer (EC) is the sixth most common cancer in women. A continued number of low-risk EC patients at diagnosis, as well as patients diagnosed with advanced-stage disease, will experience an aggressive disease. Unfortunately, those patients will present recurrence or overt dissemination. Systemic cytotoxic chemotherapy treatment on advanced, recurrent, or metastatic EC patients has shown poor results, with median survival rates of less than one year, and median progression-free survival rates of four months. Therefore, the search for innovative and alternative drugs or the development of combinatorial therapies involving new targeted drugs and standard regimens is imperative. Over the last few decades, some small-molecule inhibitors have been introduced in the clinics for cancer treatment, but only a few have been approved by the Food and Drug Administration (FDA) for EC treatment. In the present review, we present the current state and future prospects of small-molecule inhibitors on EC treatment, both alone and in combination.

EndoG influences mitochondrial DNA replication and is involved in somatic cell proliferation. Here, we investigated the effect of ENDOG/Endog expression on proliferation in different tumor models. Noteworthy, ENDOG deficiency reduced proliferation of endometrial tumor cells expressing low PTEN/high p-AKT levels, and Endog deletion blunted the growth of PTEN-deficient 3D endometrial cultures. Furthermore, ENDOG silencing reduced proliferation of follicular thyroid carcinoma and glioblastoma cell lines with high p-AKT expression. High ENDOG expression was associated with a short time to treatment in a cohort of patients with chronic lymphocytic leukemia (CLL), a B-cell lymphoid neoplasm with activation of PI3K/AKT. This clinical impact was observed in the less aggressive CLL subtype with mutated IGHV in which high ENDOG and low PTEN levels were associated with worse outcome. In summary, our results show that reducing ENDOG expression hinders growth of some tumors characterized by low PTEN activity and high p-AKT expression and that ENDOG has prognostic value for some cancer types.

Loss-of-function mutations in AT-rich interactive domain-containing protein 1 A (ARID1A), accompanied by reduced protein expression, are common in endometrial carcinoma (EC) and correlate with shorter progression-free survival. Alterations in the EC cells secretome play a critical role in shaping the tumor microenvironment (TME), thereby promoting disease progression, metastasis, and therapeutic resistance. Here, we demonstrate that ARID1A-deficient EC cells display a reprogrammed soluble secretome that alters tumor-stromal communication. Among the secreted factors, CXCL16 emerges as the predominant chemokine, promoting epithelial-to-mesenchymal transition and enhancing tumor cell invasiveness. Mechanistically, CXCL16 activates MAPK and Paxillin/FAK pathways, driving YAP/TAZ signaling and reinforcing pro-tumorigenic features. Elevated CXCL16 levels within the tumor niche also promote the conversion of stromal cells into cancer-associated fibroblasts (CAFs) in both preclinical models and patient samples of ARID1A-deficient EC. Importantly, genetic or pharmacological inhibition of CXCL16 or its receptor CXCR6 disrupts these pathogenic interactions, impairing EC cell migration and reducing metastatic burden. These findings identify the secretome of ARID1A-deficient EC cells as a key driver of tumor progression and underscore the CXCL16-CXCR6 axis as a promising therapeutic target in EC.