PO-133 Hoxa9 transcription factor: a potential novel therapeutic target in renal cell carcinoma (RCC)

Introduction Kidney cancer represents 2%–3% of all cancer cases and is an insidious cancer with poor prognosis in metastatic stages associated with chemo- and radio-resistance. Targeted therapies such as antiangiogenic or immunomodulatory agents are developed but present low response rates. Identification of new therapeutic targets for future drug development is a challenge to improve kidney cancer treatment. HOX transcription factors are interesting targets in many solid tumours and leukaemia. Particularly, HOXA9 has been associated with metastatic potential of ovarian and prostate cancers or with aggressiveness in glioblastoma or pancreas cancer. HOXA9 is normally regulated by EZH2, a frequently dysregulated/mutated actor in cancer and in renal cell carcinoma (RCC) particularly. Of interest, HOXC11, another HOX transcription factor, was previously shown to play a role in RCC. Our study aimed to investigate the role of HOXA9 in RCC and to identify if it may be an interesting therapeutic target in this cancer. Material and methods The potential role of HOXA9 in RCC was first evaluated by TCGA analysis. Then, HOXA9 was invalidated using lentivirally-expressed shRNAs, to subsequently evaluate biological impacts (survival, migration/invasion) and to perform global gene expression analysis in HOXA9-expressing RCC cell lines. In vivo , HOXA9-invalidated cells were orthotopically xenografted into immunodeficient mice and followed by bioluminescence imaging. Results and discussions TCGA analysis showed that survival rate of RCC patients who exhibit high HOXA9 expression is significantly lower compared to patients with low expression (p=0.0014). In RCC cell lines, HOXA9 invalidation led to cell death and impacted cell migration and invasion. Transcriptomic analysis identified HOXA9 regulated pathways and genes known to play a role in RCC aggressiveness. In vivo , invalidation of HOXA9 abolished tumorigenesis. Macroscopic and microscopic analyses demonstrated the absence of tumour with HOXA9-invalidated cells. Conclusion We identified HOXA9 as a novel actor of RCC tumorigenesis and aggressiveness, and propose that it could be a potential therapeutic target. These results could pave the way for new targeted therapies in kidney cancer.