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

Journal of Experimental & Clinical Cancer Research

John J. Krolewski¹  Renyuan Zhang¹  Xiang Ling²  Ieman A. M. Aljahdali³  Fengzhi Li⁴  Kent L. Nastiuk⁵ 

[1] Department of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, New York, USA;Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, New York, USA;Canget BioTekpharma LLC, 14203, Buffalo, New York, USA;Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, New York, USA;Department of Cellular & Molecular Biology, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, New York, USA;Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, New York, USA;Genitourinary Disease Site Research Group, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, New York, USA;Kidney Cancer Research Interest Group, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, New York, USA;Developmental Therapeutics (DT) Program, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, New York, USA;Genitourinary Disease Site Research Group, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, New York, USA;Department of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, New York, USA;Department of Urology, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, New York, USA;

关键词: Renal cell carcinoma (RCC);    Survivin (BIRC5);    Hypoxia inducible factor (HIF);    Nuclear factor erythroid 2-related factor 2 (NRF2);    TP53/p53;    AKT;    MCL-1;    XIAP;    MDM2;    MDM4;   

DOI  :  10.1186/s13046-021-02026-1

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY