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Vladimir F. Niculescu
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REVIEW ARTICLE

Non-genetic mechanisms of ancestral origin involved in cancer drug resistance

Vladimir F. Niculescu1*
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1 Retired Researcher, Kirschenweg, Diedorf, Germany
Tumor Discovery, 026140030 https://doi.org/10.36922/TD026140030
Received: 3 April 2026 | Revised: 21 May 2026 | Accepted: 2 June 2026 | Published online: 2 July 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Cancer progression is commonly attributed to the stepwise accumulation of somatic mutations; however, this framework does not fully account for the regulated and recurrent nature of many tumor-associated phenotypes. Here, we advance an evolutionary systems perspective in which cancer reflects the partial reactivation of conserved cellular programs that predate multicellularity. The present paper identifies conceptual and functional parallels between the cancer life cycle and that of protists, particularly parasitic species that inhabit comparable microenvironmental niches within host organisms. These parallels suggest a potential evolutionary continuity linked to a common ancestor of metazoans and amoebozoans. We hypothesize that adaptive traits originating in early historic environments—especially mechanisms conferring tolerance to oxidative stress—have been retained in the genomes of modern metazoans. Reactivation of these traits may contribute to tumor survival and progression under adverse conditions. Importantly, the occurrence of intrinsic and multidrug resistance in untreated tumors indicates that resistance is not exclusively induced by therapeutic exposure. Instead, it may arise from conserved, non-genetic stress-response programs that are activated by the tumor microenvironment. This framework provides a basis for reinterpreting cancer drug resistance as an evolutionarily embedded mechanism rather than a purely treatment-driven outcome.

Keywords
Cancer
Unicellularization
Evolution
Epigenetic protection
Transgenerational
Desensitization
Funding
None.
Conflict of interest
The author declares no conflict of interest.
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Tumor Discovery, Electronic ISSN: 2810-9775 Print ISSN: 3060-8597, Published by AccScience Publishing
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