THE EVOLUTION OF CANCER RESISTANCE AS AN INSPIRATION FOR MODERN ONCOLOGY – A REVIEW

Gabriela Kapłon; Kamila Kapłon; Barbara  Tomaszek; Aleksandra  Blok; Dominika  Gieroba; Anna  Kamieniak; Remigiusz  Flakus; Wiktor  Werenkowicz; Karolina  Glajcar

doi:10.31435/ijitss.1(49).2026.4836

Authors

Gabriela Kapłon NZOZ Przychodnia na Biskupinie Sp. z o.o., Wrocław, Poland https://orcid.org/0009-0005-1985-318X
Kamila Kapłon Medical University of Lublin, Lublin, Poland https://orcid.org/0009-0002-8355-2742
Barbara Tomaszek SPZOZ in Przeworsk, Przeworsk, Poland https://orcid.org/0009-0001-8477-0007
Aleksandra Blok SPZOZ in Przeworsk, Przeworsk, Poland https://orcid.org/0009-0001-0813-0366
Dominika Gieroba Stefan Cardinal Wyszyński Provincial Specialist Hospital SPZOZ in Lublin, Lublin, Poland https://orcid.org/0009-0006-3454-1595
Anna Kamieniak University Clinical Hospital No 4 in Lublin, Lublin, Poland https://orcid.org/0009-0006-1217-0658
Remigiusz Flakus Regional Blood Donation and Transfusion Centre in Wrocław, Wrocław, Poland https://orcid.org/0009-0008-7890-3521
Wiktor Werenkowicz Medical University of Silesia, Katowice, Poland https://orcid.org/0009-0008-8487-2426
Karolina Glajcar University Clinical Hospital in Wrocław, Wrocław, Poland https://orcid.org/0009-0007-2496-0793

DOI:

https://doi.org/10.31435/ijitss.1(49).2026.4836

Keywords:

CIRBP, Peto’s Paradox, p53 Protein, DNA Repairs Pathways, Bowhead Whale, Naked Mole-Rat

Abstract

Background: Cancer is a leading cause of mortality worldwide and is associated with the accumulation of DNA damage, disruptions in cell cycle control, and loss of genomic stability. Statistical intuition suggests that large body size or long lifespan should increase cancer risk. However, empirical observations contradict this assumption. Species such as elephants, bowhead whales, and naked mole rats do not exhibit a proportionally higher incidence of cancer, a phenomenon known as Peto's paradox.

Aim: This study aimed to compare mechanisms of cancer resistance in selected mammalian species characterized by large body size or exceptional longevity, with particular emphasis on elephants, bowhead whales, and naked mole rats. The analysis focused on DNA repair pathways, cell cycle regulation, and tumor suppressor proteins, including p53 and CIRBP.

Materials and Methods: A literature review was conducted using the PubMed, ScienceDirect, Encyclopedia Britannica, Springer and the World Health Organization. The search included the terms “CIRBP,” “Peto's paradox,” “p53 protein,” “DNA repair pathways,” “Bowhead whale,” “Cancer Resistance in Elephants,” and “Naked Mole Rat.” Only publications in English were included.

Conclusions: Comparative analysis revealed that evolution has led to diverse and effective mechanisms limiting carcinogenesis. Of particular significance is the identification of the CIRBP protein in the bowhead whale as a factor enhancing the efficiency of DNA repair, highlighting the translational potential of comparative oncology for cancer prevention and therapy.

References

Abegglen, L. M., Caulin, A. F., Chan, A., Lee, K., Robinson, R., Campbell, M. S., Kiso, W. K., Schmitt, D. L., Waddell, P. J., Bhaskara, S., Jensen, S. T., Maley, C. C., & Schiffman, J. D. (2015). Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans. JAMA, 314(17), 1850–1860. https://doi.org/10.1001/JAMA.2015.13134

Arnoult, N., & Karlseder, J. (2015). Complex interactions between the DNA-damage response and mammalian telomeres. Nature Structural & Molecular Biology, 22(11), 859–866. https://doi.org/10.1038/NSMB.3092

Aubrey, B. J., Kelly, G. L., Janic, A., Herold, M. J., & Strasser, A. (2018). How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death and Differentiation, 25(1), 104–113. https://doi.org/10.1038/CDD.2017.169

Bandaria, J. N., Qin, P., Berk, V., Chu, S., & Yildiz, A. (2016). Shelterin protects chromosome ends by compacting telomeric chromatin. Cell, 164(4), 735–746. https://doi.org/10.1016/j.cell.2016.01.036

Biechele-Speziale, D. J., Sutton, T. B., & Delaney, S. (2022). Obstacles and opportunities for base excision repair in chromatin. DNA Repair, 116, Article 103345. https://doi.org/10.1016/J.DNAREP.2022.103345

Britannica Editors. (2025, October 6). Right whale. In Encyclopedia Britannica. https://www.britannica.com/animal/right-whale

Caulin, A. F., & Maley, C. C. (2011). Peto’s paradox: Evolution’s prescription for cancer prevention. Trends in Ecology and Evolution, 26(4), 175–182. https://doi.org/10.1016/j.tree.2011.01.002

Chen, J. K., Lin, W. L., Chen, Z., & Liu, H.-W. (2018). PARP-1-dependent recruitment of cold-inducible RNA-binding protein promotes double-strand break repair and genome stability. Proceedings of the National Academy of Sciences of the United States of America, 115(8), E1759–E1768. https://doi.org/10.1073/PNAS.1713912115

Chen, L., Liu, S., & Tao, Y. (2020). Regulating tumor suppressor genes: Post-translational modifications. Signal Transduction and Targeted Therapy, 5(1), Article 90. https://doi.org/10.1038/S41392-020-0196-9

Chen, Y., Chen, Z., Wang, H., Cui, Z., Li, K. L., Song, Z., Chen, L., Sun, X., Xu, X., Zhang, Y., Tan, L., Yuan, J., Tan, R., Luo, M.-H., Sun, F.-L., Liu, H., Jiang, Y., & Mao, Z. (2025). A cGAS-mediated mechanism in naked mole-rats potentiates DNA repair and delays aging. Science, 390(6769). https://doi.org/10.1126/SCIENCE.ADP5056

Diotti, R., & Loayza, D. (2011). Shelterin complex and associated factors at human telomeres. Nucleus, 2(2). https://doi.org/10.4161/NUCL.2.2.15135

Efeyan, A., & Serrano, M. (2007). p53: Guardian of the genome and policeman of the oncogenes. Cell Cycle, 6(9), 1006–1010. https://doi.org/10.4161/CC.6.9.4211

Firsanov, D., Zacher, M., Tian, X., Sformo, T. L., Zhao, Y., Tombline, G., Lu, J. Y., Zheng, Z., Perelli, L., Gurreri, E., Zhang, L., Guo, J., Korotkov, A., Volobaev, V., Biashad, S. A., Zhang, Z., Heid, J., Maslov, A., Sun, S., ... Gorbunova, V. (2024). DNA repair and anti-cancer mechanisms in the long-lived bowhead whale. bioRxiv. https://doi.org/10.1101/2023.05.07.539748

Firsanov, D., Zacher, M., Tian, X., Sformo, T. L., Zhao, Y., Tombline, G., Lu, J. Y., Zheng, Z., Perelli, L., Gurreri, E., Zhang, L., Guo, J., Korotkov, A., Volobaev, V., Biashad, S. A., Zhang, Z., Heid, J., Maslov, A. Y., Sun, S., ... Gorbunova, V. (2025). Evidence for improved DNA repair in the long-lived bowhead whale. Nature. https://doi.org/10.1038/S41586-025-09694-5

Garemilla, S. S. S., Kadambala, M. C., Gampa, S. C., Chinthala, S., & Garimella, S. V. (2025). Cancer metastasis: Therapeutic challenges and opportunities. Medical Oncology, 42(11). https://doi.org/10.1007/S12032-025-03072-X

Gartner, A., & Engebrecht, J. (2021). DNA repair, recombination, and damage signaling. Genetics, 220(2), Article iyab178. https://doi.org/10.1093/GENETICS/IYAB178

Gohil, D., Sarker, A. H., & Roy, R. (2023). Base excision repair: Mechanisms and impact in biology, disease, and medicine. International Journal of Molecular Sciences, 24(18), Article 14186. https://doi.org/10.3390/IJMS241814186

Hadi, F., Smith, E. S. J., & Khaled, W. T. (2021). Naked mole-rats: Resistant to developing cancer or good at avoiding it? In Advances in Experimental Medicine and Biology (Vol. 1319, pp. 341–352). https://doi.org/10.1007/978-3-030-65943-1_14

Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144(5), 646–674. https://doi.org/10.1016/J.CELL.2011.02.013

Hernández Borrero, L. J., & El-Deiry, W. S. (2021). Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochimica et Biophysica Acta - Reviews on Cancer, 1876(1). https://doi.org/10.1016/j.bbcan.2021.188556

Kitajima, S., & Takahashi, C. (2017). Intersection of retinoblastoma tumor suppressor function, stem cells, metabolism, and inflammation. Cancer Science, 108(9), 1726–1731. https://doi.org/10.1111/CAS.13312

Lagunas-Rangel, F. A. (2021). Deciphering the whale’s secrets to have a long life. Experimental Gerontology, 151. https://doi.org/10.1016/j.exger.2021.111425

Lin, T. D., Rubinstein, N. D., Fong, N. L., Smith, M., Craft, W., Martin-McNulty, B., Perry, R., Delaney, M. A., Roy, M. A., & Buffenstein, R. (2024). Evolution of T cells in the cancer-resistant naked mole-rat. Nature Communications, 15, Article 3145. https://doi.org/10.1038/s41467-024-47264-x

Maciak, S. (2022). Cell size, body size and Peto’s paradox. BMC Ecology and Evolution, 22, Article 142. https://doi.org/10.1186/S12862-022-02096-5

Mir, S. M., Tehrani, S. S., Goodarzi, G., Jamalpoor, Z., Asadi, J., Khelghati, N., Qujeq, D., & Maniati, M. (2020). Shelterin complex at telomeres: Implications in ageing. Clinical Interventions in Aging, 15, 827–839. https://doi.org/10.2147/CIA.S256425

Palefsky, E., Patel, H. K., Doss, T. A., Eischeid, E. C., Lee, P., Durkee, M. A., Yang, W. H., Duncan, A. M., Patel, D., Patel, A. P., Yang, W. H., & Lee, J. H. (2025). Characterizing elephant MDM2’s role in p53 regulation. FASEB Journal, 39(19), Article e71093. https://doi.org/10.1096/FJ.202502511R

Rana, S., Jogi, M. K., Choudhary, S., Thakur, R., Sahoo, G. C., & Joshi, V. (2024). Unraveling the intricacies of cold-inducible RNA-binding protein: A comprehensive review. Cell Stress & Chaperones, 29(4), 615. https://doi.org/10.1016/J.CSTRES.2024.07.001

Sanchez Sanchez, G., Emmrich, S., Georga, M., Papadaki, A., Kossida, S., Seluanov, A., Gorbunova, V., & Vermijlen, D. (2024). Invariant γδTCR natural killer-like effector T cells in the naked mole-rat. Nature Communications, 15(1). https://doi.org/10.1038/S41467-024-48652-Z

Shepard, A., Lester, D. K., Troutman, S., Hoxha, S., Khaled, W. T., Smith, E. S. J., Park, T. J., Buffenstein, R., Du, D., Teng, M., Dengler-Crish, C. M., Tsai, K. Y., Flores, E. R., Ventura, A., & Kissil, J. L. (2025). An autochthonous model of lung cancer identifies requirements for cellular transformation in the naked mole-rat. Cancer Discovery, OF1–OF11. https://doi.org/10.1158/2159-8290.CD-25-0526

Shoshani, J. (2025, December 3). Elephant. In Encyclopedia Britannica. https://www.britannica.com/animal/elephant-mammal

Simabuco, F. M., Morale, M. G., Pavan, I. C. B., Morelli, A. P., Silva, F. R., & Tamura, R. E. (2018). p53 and metabolism: From mechanism to therapeutics. Oncotarget, 9(34), 23780–23823. https://doi.org/10.18632/ONCOTARGET.25267

Smith, E. M., Pendlebury, D. F., & Nandakumar, J. (2020). Structural biology of telomeres and telomerase. Cellular and Molecular Life Sciences, 77(1), 61–79. https://doi.org/10.1007/S00018-019-03369-X

Sulak, M., Fong, L., Mika, K., Chigurupati, S., Yon, L., Mongan, N. P., Emes, R. D., & Lynch, V. J. (2016). TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. eLife, 5, Article e11994. https://doi.org/10.7554/ELIFE.11994

Sun, L., Xu, Z., Shuai, M., Li, C., Yang, G., & Xu, S. (2025). Natural resistance to cancers in long-lived mammals: Genomic mechanisms and experimental evidence to explain Peto’s paradox. Science China Life Sciences, 68(6), 1801–1814. https://doi.org/10.1007/S11427-024-2838-X

Sutton, T. B., Sawyer, D. L., Naila, T., Sweasy, J. B., Tomkinson, A. E., & Delaney, S. (2024). Global screening of base excision repair in nucleosome core particles. DNA Repair, 144, Article 103777. https://doi.org/10.1016/J.DNAREP.2024.103777

Szasz, A. (2024). Peto’s “paradox” and six degrees of cancer prevalence. Cells, 13(2). https://doi.org/10.3390/CELLS13020197

Tollis, M., Boddy, A. M., & Maley, C. C. (2017). Peto’s paradox: How has evolution solved the problem of cancer prevention? BMC Biology, 15, Article 60. https://doi.org/10.1186/S12915-017-0401-7

Tyshkovskiy, A., Ma, S., Shindyapina, A. V., Tikhonov, S., Lee, S. G., Bozaykut, P., Castro, J. P., Seluanov, A., Schork, N. J., Gorbunova, V., Dmitriev, S. E., Miller, R. A., & Gladyshev, V. N. (2023). Distinct longevity mechanisms across and within species and their association with aging. Cell, 186(13), 2929. https://doi.org/10.1016/J.CELL.2023.05.002

Vijg, J., & Suh, Y. (2013). Genome instability and aging. Annual Review of Physiology, 75, 645–668. https://doi.org/10.1146/ANNUREV-PHYSIOL-030212-183715

Wang, R., Sun, Y., Li, C., Xue, Y., & Ba, X. (2023). Targeting the DNA damage response for cancer therapy. International Journal of Molecular Sciences, 24(21). https://doi.org/10.3390/IJMS242115907

Waters, K. L., & Spratt, D. E. (2024). New discoveries on protein recruitment and regulation during the early stages of the DNA damage response pathways. International Journal of Molecular Sciences, 25(3). https://doi.org/10.3390/IJMS25031676

World Health Organization. (2025, February 3). Cancer. https://www.who.int/news-room/fact-sheets/detail/cancer

Xia, P., & Xu, X.-Y. (2023). Use of tumor suppressor genes of naked mole rats for human cancer treatment. American Journal of Translational Research, 15(8), 5356. https://pmc.ncbi.nlm.nih.gov/articles/PMC10492090/

Yamasaki, L. (2003). Role of the RB tumor suppressor in cancer. Cancer Treatment and Research, 115, 209–239. https://doi.org/10.1007/0-306-48158-8_9

Zhang, Z., Tian, X., Lu, J. Y., Boit, K., Ablaeva, J., Zakusilo, F. T., Emmrich, S., Firsanov, D., Rydkina, E., Biashad, S. A., Lu, Q., Tyshkovskiy, A., Gladyshev, V. N., Horvath, S., Seluanov, A., & Gorbunova, V. (2023). Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice. Nature, 621(7977), 196–205. https://doi.org/10.1038/S41586-023-06463-0

Zhao, S., Tadesse, S., & Kidane, D. (2021). Significance of base excision repair to human health. International Review of Cell and Molecular Biology, 364, 163–193. https://doi.org/10.1016/BS.IRCMB.2021.05.002