Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma.

ABSTRACT

The incidence of renal cell carcinoma (RCC) is increasing worldwide with an approximate 20% mortality rate. The challenge in RCC is the therapy-resistance. Cancer resistance to treatment employs multiple mechanisms due to cancer heterogeneity with multiple genetic and epigenetic alterations. These changes include aberrant overexpression of (1) anticancer cell death proteins (e.g., survivin/BIRC5), (2) DNA repair regulators (e.g., ERCC6) and (3) efflux pump proteins (e.g., ABCG2/BCRP); mutations and/or deregulation of key (4) oncogenes (e.g., MDM2, KRAS) and/or (5) tumor suppressor genes (e.g., TP5/p53); and (6) deregulation of redox-sensitive regulators (e.g., HIF, NRF2). Foci of tumor cells that have these genetic alterations and/or deregulation possess survival advantages and are selected for survival during treatment. We will review the significance of survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, TP5/p53, KRAS and AKT in treatment resistance as the potential therapeutic biomarkers and/or targets in RCC in parallel with our analized RCC-relevant TCGA genetic results from each of these gene/protein molecules. We then present our data to show the anticancer drug FL118 modulation of these protein targets and RCC cell/tumor growth. Finally, we include additional data to show a promising FL118 analogue (FL496) for treating the specialized type 2 papillary RCC.