Intratumoral heterogeneity and consequences for targeted therapies

Abstract

SummaryAccording 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. Mots clés Mutation génétiqueRechute tumorale Résistance aux médicaments Protéomique MALDI-TOF RésuméHétérogénéité intratumorale : impact sur le développement de therapies ciblées Selon le principe de la sélection clonale, dérivée de la théorie de l'évolution énoncée par Darwin, les cellules cancéreuses sont capables d'évoluer et d'acquérir de nouvelles mutations. Ces mutations permettent d'améliorer à la fois leurs aptitudes à proliférer, migrer et envahir les tissus environnants, de même que leur capacité à former des métastases. Des études récentes, dans le domaine de la génétique, démontrent que, lorsqu'elles sont diagnostiquées à temps, les masses tumorales sont constituées d'une vaste population hétérogène de cellules, qui présentent entre elles une variabilité considérable de mutations. Cette hétérogénéité génétique au niveau cellulaire se traduit généralement par une importante capacité des cellules cancéreuses à s'adapter à tout environnement, aussi hostile soit-il, et représente un obstacle majeur au succès des thérapies ciblées, qui, par définition, se concentrent sur une voie de signalisation ou une

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Heterogeneity in Lung Cancer

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