Genetic and non-genetic drug resistance: Darwin or Lamarck?

Abstract

Drug resistance represents a major limitation to the long-term efficacy of anti-cancer treatments. The commonly accepted view is that the selection of inheritable genetic mechanisms governs the development of secondary resistance. However, compelling evidence suggests an important role for adaptive cell plasticity and non-genetic mechanisms in the development of therapy resistance. The two phenomena are not mutually exclusive and the interplay between genetic and non-genetic mechanisms may affect tumor evolution during treatment. A broader characterization of the genetic and non-genetic mechanisms of drug resistance may pave the way for more precise and effective therapeutic strategies to overcome resistance.

Keywords: drug resistance; epigenetic; genetic; tumor evolution.

Fig. 1

Genetic and non‐genetic mechanisms drive resistance to anti‐cancer therapy. Tumors may display genetic and/or non‐genetic intra tumor heterogeneity (ITH). Genetically drug‐resistant cancer cells, responsible for tumor recurrence, may be present in the tumor lesion before drug administration (upper panel). Pre‐existing (middle panel) or drug‐induced (lower panel) non‐genetic phenotype(s) may provide a fitter cellular state capable of tolerating drug exposure and drive drug resistance. Adaptive non‐genetic phenotype may favor the acquisition of genetic mechanism(s) of drug resistance (lower panel). Figure was created with BioRender.com.