The role of the RNA demethylase FTO in metabolic reprogramming of renal cell carcinoma

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Abstract Kidney cancer is increasing in prevalence and is one of the top 10 most common cancers world-wide. Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of kidney cancer. While primary ccRCC is treated with surgery, 30% of patients are diagnosed with regionally advanced or metastatic disease that requires systemic therapy. Despite current treatments that target the tumor microenvironment, the 5-year survival rate for advanced ccRCC remains 11%. HIF-2 plays an important oncogenic role in ccRCC, which has led to the recent development of the HIF-2 inhibitor belzutifan. However, innate and acquired resistance limits durable responses in the majority of patients. Thus, there is a need to identify additional therapeutic targets that directly inhibit the growth and survival of ccRCC cancer cells. The von Hippel Lindau (VHL) tumor suppressor gene is lost in ccRCC tumors associated with the VHL disease and in 90% of sporadic ccRCC tumors. Hallmark features of VHL deficient ccRCC include constitutive activation of hypoxic (HIF) signaling, angiogenesis and metabolic reprogramming. We recently discovered a synthetic lethal interaction between the RNA demethylase FTO and VHL in ccRCC. Importantly, FTO knockdown reduces ccRCC growth and survival independent of HIF-2. Yet, actionable mechanistic insights into 1) how FTO promotes VHL deficient ccRCC growth and survival and 2) the therapeutic potential of FTO-based therapy in ccRCC are critical gaps in knowledge addressed in this application. Our central hypothesis is that the m6A RNA demethylase, fat-mass and obesity-associated protein (FTO), promotes glutamine reprogramming to support the growth of belzutifan sensitive and resistant ccRCC. Our specific aims will test the following hypotheses: (Aim1) FTO promotes VHL deficient ccRCC glutamine reprogramming by increasing the expression of the glutamine transporter SLC1A5 via m6A demethylation; (Aim 2) FTO inhibitors create a metabolic vulnerability in VHL deficient ccRCC that can be exploited therapeutically to treat belzutifan sensitive and resistant tumors. Upon conclusion, we will understand the role of m6A RNA methylation and FTO as epitranscriptomic regulators of glutamine reprogramming in ccRCC. This contribution is significant since it will establish that SLC1A5, an actionable and prognostic cancer therapy target, is regulated by FTO through m6A modifications. Additionally, insight into the mechanisms of FTO- mediated growth, survival and glutamine reprogramming is important for the rapid translation of precision medicine approaches as FTO inhibitors are currently in clinical development.