Navigating Nongenetic Plasticity in Cancer Drug Resistance

Nongenetic plasticity has emerged as a key driver of cancer drug resistance, yet its precise origins, nature, and consequences are not fully clarified. This review examines technological, computational, and conceptual developments in the nongenetic determinants of drug resistance. We begin by proposing refined definitions of cellular state, fate, and plasticity. We subsequently contextualize the findings from multimodal approaches to investigate plasticity, highlighting how new single-cell lineage-tracing methods provide opportunities for quantitatively capturing state transitions, their timescales and heritability, and how they contribute to resistance mechanisms. We also draw parallels with concepts from developmental biology and microbial persistence research. Next, we cover the role that computational approaches have played in revealing the otherwise latent patterns of heterogeneity that underlie plasticity from complex datasets. We conclude by emphasizing the need for standardized terminology in this rapidly evolving field and the path from bench to bedside.