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

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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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13046-021-02026-1.

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Most cited references 189

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Cancer statistics, 2020

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2020)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.

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Cancer Statistics, 2021

Rebecca Siegel, Kimberly D Miller, Hannah Fuchs … (2021)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2017) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2018) were collected by the National Center for Health Statistics. In 2021, 1,898,160 new cancer cases and 608,570 cancer deaths are projected to occur in the United States. After increasing for most of the 20th century, the cancer death rate has fallen continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment. This translates to 3.2 million fewer cancer deaths than would have occurred if peak rates had persisted. Long-term declines in mortality for the 4 leading cancers have halted for prostate cancer and slowed for breast and colorectal cancers, but accelerated for lung cancer, which accounted for almost one-half of the total mortality decline from 2014 to 2018. The pace of the annual decline in lung cancer mortality doubled from 3.1% during 2009 through 2013 to 5.5% during 2014 through 2018 in men, from 1.8% to 4.4% in women, and from 2.4% to 5% overall. This trend coincides with steady declines in incidence (2.2%-2.3%) but rapid gains in survival specifically for nonsmall cell lung cancer (NSCLC). For example, NSCLC 2-year relative survival increased from 34% for persons diagnosed during 2009 through 2010 to 42% during 2015 through 2016, including absolute increases of 5% to 6% for every stage of diagnosis; survival for small cell lung cancer remained at 14% to 15%. Improved treatment accelerated progress against lung cancer and drove a record drop in overall cancer mortality, despite slowing momentum for other common cancers.

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Cancer statistics, 2019

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2019)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006-2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007-2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2-fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012-2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.

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Author and article information

Contributors

Fengzhi Li:

ORCID: http://orcid.org/0000-0002-2299-7951

fengzhi.li@roswellpark.org

Ieman A. M. Aljahdali: ieman.aljahdali@RoswellPark.org

Renyuan Zhang: Renyuan.Zhang@RoswellPark.org

Kent L. Nastiuk: Kent.Nastiuk@RoswellPark.org

John J. Krolewski: John.Krolewski@RoswellPark.org

Xiang Ling: Xiang.Ling@RoswellPark.org

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J Exp Clin Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 12 August 2021

Publication date PMC-release: 12 August 2021

Publication date Collection: 2021

Volume: 40

Electronic Location Identifier: 254

Affiliations

[1 ]GRID grid.240614.5, ISNI 0000 0001 2181 8635, Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, ; Buffalo, New York 14263 USA

[2 ]GRID grid.240614.5, ISNI 0000 0001 2181 8635, Genitourinary Disease Site Research Group, Roswell Park Comprehensive Cancer Center, ; Buffalo, New York 14263 USA

[3 ]GRID grid.240614.5, ISNI 0000 0001 2181 8635, Kidney Cancer Research Interest Group, Roswell Park Comprehensive Cancer Center, ; Buffalo, New York 14263 USA

[4 ]GRID grid.240614.5, ISNI 0000 0001 2181 8635, Developmental Therapeutics (DT) Program, Roswell Park Comprehensive Cancer Center, ; Buffalo, New York 14263 USA

[5 ]GRID grid.240614.5, ISNI 0000 0001 2181 8635, Department of Cellular & Molecular Biology, Roswell Park Comprehensive Cancer Center, ; Buffalo, New York 14263 USA

[6 ]GRID grid.240614.5, ISNI 0000 0001 2181 8635, Department of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, ; Buffalo, New York 14263 USA

[7 ]GRID grid.240614.5, ISNI 0000 0001 2181 8635, Department of Urology, Roswell Park Comprehensive Cancer Center, ; Buffalo, New York 14263 USA

[8 ]GRID grid.504273.7, Canget BioTekpharma LLC, ; Buffalo, New York 14203 USA

Author information

Fengzhi Li http://orcid.org/0000-0002-2299-7951

Article

Publisher ID: 2026

DOI: 10.1186/s13046-021-02026-1

PMC ID: 8359575

PubMed ID: 34384473

SO-VID: 9ce36a84-2640-4271-9da6-f32f51819f69

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 13 May 2021

Date accepted : 21 June 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100001784, Pancreatic Cancer Action Network;

Award ID: 20-65-FENG

Award Recipient : Fengzhi Li

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: 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

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: 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

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

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Supplementary Information

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Journal of Circulating Biomarkers

Most cited references 189

Cancer statistics, 2020

Cancer Statistics, 2021

Cancer statistics, 2019

Author and article information

Contributors

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