Evolutionary dynamics of carcinogenesis and why targeted therapy does not work.

All malignant cancers, whether inherited or sporadic, are fundamentally governed by Darwinian dynamics. The process of carcinogenesis requires genetic instability and highly selective local microenvironments, the combination of which promotes somatic evolution. These microenvironmental forces, specifically hypoxia, acidosis and reactive oxygen species, are not only highly selective, but are also able to induce genetic instability. As a result, malignant cancers are dynamically evolving clades of cells living in distinct microhabitats that almost certainly ensure the emergence of therapy-resistant populations. Cytotoxic cancer therapies also impose intense evolutionary selection pressures on the surviving cells and thus increase the evolutionary rate. Importantly, the principles of Darwinian dynamics also embody fundamental principles that can illuminate strategies for the successful management of cancer.