Cancer evolution: Darwin and beyond

Abstract

Clinical and laboratory studies over recent decades have established branched evolution as a feature of cancer. However, while grounded in somatic selection, several lines of evidence suggest a Darwinian model alone is insufficient to fully explain cancer evolution. First, the role of macroevolutionary events in tumour initiation and progression contradicts Darwin's central thesis of gradualism. Whole-genome doubling, chromosomal chromoplexy and chromothripsis represent examples of single catastrophic events which can drive tumour evolution. Second, neutral evolution can play a role in some tumours, indicating that selection is not always driving evolution. Third, increasing appreciation of the role of the ageing soma has led to recent generalised theories of age-dependent carcinogenesis. Here, we review these concepts and others, which collectively argue for a model of cancer evolution which extends beyond Darwin. We also highlight clinical opportunities which can be grasped through targeting cancer vulnerabilities arising from non-Darwinian patterns of evolution.

Keywords: cancer; cancer evolution; cancer therapy; tumour heterogeneity.

Figure 1. Models of tumour evolution

Models of linear evolution (A), branched evolution (B), macroevolution (C) and neutral evolution (D) described by Muller plots representing dynamic changes in clonal size over time (left), clonal lineages and phylogenetic trees (centre) and changes in the number of alterations over time (right). Colours indicate different clones.

Figure 2. Scales of tumour evolution

Schematic illustration of the different determinants of tumour evolution, which influence evolutionary trajectories through highly interdependent mechanisms, from a microscopic (left) to a macroscopic (right) scale.

Figure 3. Evolutionary‐based treatment strategies

(A) Most conventional therapeutic approaches will lead to marked initial responses but often fail to eliminate—or induce the emergence of—drug‐tolerant cells. This population of minimal residual disease (MRD) represents a reservoir of malignant cells from which drug‐resistant clone(s) may emerge and cause tumour relapse. (B) In adaptive therapy, treatment is discontinued upon reaching a pre‐defined threshold so as not to eliminate all drug‐sensitive cells (dark grey). These cells are then allowed to grow back and are expected to suppress the growth of drug‐tolerant (or therapy‐resistant) clones owing to their higher fitness upon withdrawal. (C) Collateral sensitivities, wherein acquisition of resistance to a first drug induces susceptibility to a second one, can be exploited to target cancer‐specific vulnerabilities and potentially lead to tumour eradication. (D) In the Sucker’s gambit, the first drug forces a phenotypic adaptation that pushes tumour cells into an evolutionary trap by increasing the fitness of a highly drug‐sensitive population (leading to its clonal dominance), which is then eliminated by a second line of treatment. (E) Limiting drug adaptation may prevent the establishment of drug‐tolerant (MRD) and drug‐resistant populations. In this setting, a combination of drugs is used to simultaneously eradicate tumour cells and to prevent the emergence of drug‐induced adaptive responses.