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Updated: Sep 29, 2025
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Integrating mutational and nonmutational mechanisms of acquired therapy resistance within the Darwinian paradigm
Robert Vander Velde1, Sydney Shaffer1, Andriy Marusyk2
1Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
Abstract:
Mutational processes and nongenetic phenotypic state transitions represent distinct paradigms for understanding acquired resistance to targeted therapies. While ample empirical evidence supports both paradigms, they are typically viewed as mutually exclusive. However, a growing body of evidence points to the multifactorial nature of resistance, where resistant tumor cell phenotypes integrate the influence of multiple mutational and epigenetic changes. This leads to growing calls for a conceptual framework capable of incorporating the effects of genetic and nongenetic mechanisms. Here, we argue that the original Darwinian paradigm centered on the concept of natural selection, rather than its mutation-centric reinterpretation, might provide the optimal backbone for a much-needed synthesis.
Insights
Acquired resistance to targeted therapies involves both genetic mutations and nongenetic changes. A unified framework, rooted in Darwinian natural selection, can better explain how these diverse mechanisms interact to drive tumor evolution.
Area of Science:
- Oncology
- Evolutionary Biology
- Genetics
Background:
- Acquired resistance to targeted therapies is a major clinical challenge.
- Two main paradigms explain resistance: genetic mutations and nongenetic phenotypic state transitions.
- These paradigms are often viewed as mutually exclusive.
Purpose of the Study:
- To propose a conceptual framework for understanding acquired resistance.
- To integrate the effects of both genetic and nongenetic mechanisms of resistance.
- To argue for a Darwinian natural selection-based approach for synthesis.
Main Methods:
- Conceptual analysis and synthesis of existing evidence.
- Review of literature on tumor resistance mechanisms.
- Theoretical modeling of evolutionary dynamics in cancer.
Main Results:
- Evidence suggests resistance is multifactorial, involving combined genetic and nongenetic changes.
- Tumor cell phenotypes in resistant states integrate multiple mutational and epigenetic influences.
- A unified framework is needed to incorporate diverse resistance mechanisms.
Conclusions:
- The original Darwinian paradigm of natural selection offers an optimal backbone for synthesizing genetic and nongenetic resistance mechanisms.
- Rethinking resistance through a natural selection lens can advance therapeutic strategies.
- A comprehensive understanding of resistance requires integrating evolutionary principles.
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