HOX genes are a group of 39 genes known best for their role in embryonal development. Their function in oncogenesis is an exciting and rapidly developing field. They have been shown to be important in proliferation, epithelial-to-mesenchymal transition and Platinum resistance in other types of cancer, but this is the first study of their role in endometrioid ovarian cancer.
HOX gene expression was examined in endometrioid ovarian cancer cell lines and tissue using public databanks. This was then verified using Nanostring gene expression assays in a cohort of 56 FFPE samples from patients with EOC. Immunohistochemistry using HOX antibodies was also used to validate gene expression data. HXR9, a small molecule inhibitor of HOX, was used to test the sensitivity of EOC cell line TOV-112D to HOX inhibition using the MTS cell proliferation assay and Incucyte live cell analysis system. HXR9 was also tested for synergy with Platinum chemotherapy using a BLISS analysis and the ability to reverse platinum reistance using a colony formation assay.
Widespread HOX gene dysregulation was observed in public databanks in both EOC cell lines and tumour tissue. This was mirrored in my cohort of 56 patients with EOC. In particular, HOX B5 was over-expressed and HOX D10 was under-expressed in both RNA expression assays and at a protein level. However, there was no correlation between HOX gene expression and clinico-pathological variable such as stage, grade, time to progression or overall survival. HXR9 was able to effectively kill TOV-112D cells with an IC50 40uM. HXR9 worked in synergy with Cisplatin to kill more cells with BLISS values > 10. HXR9 was able to overcome Platinum resistance in the colony formation assay.
HOX genes are dysregulated in endometrioid ovarian cancer and can be targeted for therapeutic purposes. HXR9 is able to kill EOC in a cell line model and work synergistically with Platinum chemotherapy, helping to overcome platinum resistance which is the number one clinical challenge facing patients with advanced ovarian cancer.
University of Surrey.
GRACE Charity.
All authors have declared no conflicts of interest.