Intratumoral heterogeneity and consequences for targeted therapies.

According to the clonal model and Darwinian evolution, cancer cell evolves through new mutations helping it to proliferate, migrate, invade and metastasize. Recent genetic studies have clearly shown that tumors, when diagnosed, consist of a large number of mutations distributed in different cells. This heterogeneity translates in substantial genetic plasticity enabling cancer cells to adapt to any hostile environment. As targeted therapy focuses only on one pathway or protein, there will always be a cell with the "right" genetic background to survive the treatment and cause tumor relapse. Because today's targeted therapies never took tumor heterogeneity into account, nearly all novel drugs fail to provide patients with a considerable improvement of the survival. However, emerging proteomic studies guided by the idea that Darwinian selection is governed by the phenotype and not genotype, show that heterogeneity at the protein level is much less complex, then it could be expected from genetic studies. This information together with the recent trend to switch from functional to cytotoxic targeting may offer an entirely new strategy to efficiently combat cancer.