Tumour growth and drug resistance: an evolutionary view with perspectives in therapeutics
Résumé
BACKGROUND Drug-induced drug resistance in cancer has
been attributed to diverse biological mechanisms at the individual
cell or cell population scale, relying on stochastically or epigenetically
varying expression of phenotypes at the single cell level,
and on the adaptability of tumours at the cell population level.
SCOPE OF THIS REVIEW We focus on intra-tumour heterogeneity,
namely between-cell variability within cancer cell populations,
to account for drug resistance. To shed light on such heterogeneity,
we review evolutionary mechanisms that encompass
the great evolution that has designed multicellular organisms, as
well as smaller windows of evolution on the time scale of human
disease. We also present mathematical models used to predict
drug resistance in cancer and optimal control methods that can
circumvent it in combined therapeutic strategies.
MAJOR CONCLUSIONS Plasticity in cancer cells, i.e., partial
reversal to a stem-like status in individual cells and resulting
adaptability of cancer cell populations, may be viewed as backward
evolution making cancer cell populations resistant to drug
insult. This reversible plasticity is captured by mathematical models
that incorporate between-cell heterogeneity through continuous
phenotypic variables. Such models have the benefit of being
compatible with optimal control methods for the design of optimised
therapeutic protocols involving combinations of cytotoxic
and cytostatic treatments with epigenetic drugs and immunotherapies.
GENERAL SIGNIFICANCE Gathering knowledge from cancer
and evolutionary biology with physiologically based mathematical
models of cell population dynamics should provide oncologists
with a rationale to design optimised therapeutic strategies
to circumvent drug resistance, that still remains a major pitfall of
cancer therapeutics.
Origine | Fichiers produits par l'(les) auteur(s) |
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