Epigenetics in advanced renal cell carcinoma: Potential new targets

Kidney cancer represents the third tumor most frequently diagnosed in the urinary tract in adults. The clear cell subtype is the most common one, representing approximately 85–90 % of all renal cancer diagnoses (Urinary and Male Genital Tumours, 2018). In Europe, the incidence of renal cell carcinoma (RCC) accounts for about 84,000 new cases per year with a mortality rate of about 35,000 patients (Sung et al., 2021). In recent years, incidence has increased in the early stages and only one out of five patients will present metastases at diagnosis. Approximately 20–40 % of patients will relapse within 5 years, despite radical treatment for localized disease. In addition, the mortality rate tends to stabilize or even decline in Northern and Eastern Europe, Australia and US, during the last decades.

Padala et al., (2020); Palumbo et al., (2021).

Nowadays, the main prognostic factors used in clinical practice are related to histological and clinical data: Fuhrman grade, node involvement, metastatic sites, the possibility of complete tumor resection, ECOG performance status and analytical values (Zheng et al., 2020). Despite efforts, no accurate biomarker has already been defined for early diagnosis, prognosis, and prediction of response, partly due to RCC heterogeneity (Costa-Pinheiro et al., 2015, Solano-Iturri et al., 2020). Surgery is the main therapeutic option in locally or locally advanced disease (Mir et al., 2017). Currently, new drugs are coming in the field of the adjuvant setting as sunitinib was firstly approved by the Food and Drug Administration (FDA) based on the results of the S-TRAC trial and, more recently, pembrolizumab has also been approved by the FDA and the European Medicines Agency (EMA) based on the results of the Keynote-564 trial. Pembrolizumab has shown a significant benefit in disease free survival, with tolerable adverse events, waiting for final overall survival results (Choueiri et al., 2021a).

VHL mutations have been described in these tumors that lead to the inactivation of Von Hippel-Lindau (VHL) and trigger the stabilization of HIF1A-HIF2A to increase the hypoxia response-related genes transcription. This downstream signaling ends in aberrant angiogenesis and tumor progression (Kaelin, 2002, de Paulsen et al., 2001). As a result, many small molecules such as tyrosine kinase inhibitors (TKI) have been developed to change the natural history of kidney cancer, such as sunitinib, pazopanib, axitinib, cabozantinib, lenvatinib, sorafenib or tivozanib (Morais, 2014, Motzer et al., 2007, Motzer et al., 2013, Hutson et al., 2013, Choueiri et al., 2016, Motzer et al., 2015, Escudier et al., 2007, Rini et al., 2020). Other strategies used in the past targeting mTOR in monotherapy are currently in disuse.

In addition, the development of immune checkpoint inhibitors (ICI) based on the immunosuppressive tumor microenvironment has changed the paradigm of ccRCC treatment. To summarize, a double combination of ICI, such as nivolumab/ipilimumab, or with antiangiogenic agents, such as pembrolizumab/axitinib, nivolumab/cabozantinib or pembrolizumab/lenvatinib are the approved options that have led this change in the first line setting of the advanced disease (Albiges et al., 2019, Jonasch, 2019, Motzer et al., 2019, Angulo and Shapiro, 2019, Motzer et al., 2018, Rini et al., 2019, Choueiri et al., 2021b, Motzer et al., 2021). Additionally, most patients will receive subsequent treatment lines and the choice of therapy at relapse depends on prior therapy, but no biomarker has been defined to guide this decision. This refractory setting needs the development of new treatment strategies for patients progressing or not responding to antiangiogenics and ICI as an unmet clinical need.

In RCC, it is not common to find gene mutations frequently involved in other solid tumors, such as RAS, TP53, RB or PTEN. However, in the past decade, exome sequencing identified frequently mutated genes involved in kidney cancer, such as SETD2 (SET domain containing 2, histone methyl transferase) in 3–12 % of patients, KDM5C (Lysine Demethylase 5 C) in 3– 8% of patients, KDM6A (lysine demethylase 6 A) in 1 % of patients, BAP1 (associated protein 1-BAP1) in 10–15 %of patients and PBRM1 (polybromo 1, a nucleosome remodeling complex component) in21–41 %of patients, that participate in histone or micro-RNA expression (Dalgliesh et al., 2010a, Sato et al., 2013, Guo et al., 2012, Hakimi et al., 2013a, Hakimi et al., 2013b). Epigenetic aberrations are commonly found in RCC, showing that changes in epigenetic modifications, like promoter methylation or abnormal microRNA expression, are key in the development of RCC due to gene expression alterations without changes in the genome sequence. These alterations are conditioning the prognosis of patients with advanced RCC and might be potential predictive biomarkers as well as potential targets for drug development (Cubas and Rathmell, 2018, Joosten et al., 2018).

Overall, this review aims to summarize the main epigenetic alterations found in RCC and their involvement in cell signaling pathways, as well as potential future clinical implications. For this purpose, relevant literature was searched in PubMed database published between the years 2000 and 2022, using the combination of the terms “epigenetic”, “kidney cancer or renal cell carcinoma” as well as “HDAC”, “DNMT”, “EZH2″ or “BET”.

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