Genotype- or Phenotype-Targeting Anticancer Therapies? Lessons from Tumor Evolutionary Biology

Despite the efficacy of most cancer therapies, drug resistance remains a major problem in the clinic. The eradication of the entire tumor and the cure of the patient by chemotherapy alone are rare, in particular for advanced disease. From an evolutionary perspective, the selective pressure exerted by chemotherapy leads to the emergence of resistant clones where resistance can be associated with many different functional mechanisms at the single cell level or can involve changes in the tumor micro-environment. In the last decade, tumor genomics has contributed to the improvement of our understanding of tumorigenesis and has led to the identification of numerous cellular targets for the development of novel therapies. However, since tumors are by nature extremely heterogeneous, the drug efficacy and economical sustainability of this approach is now debatable. Importantly, tumor cell heterogeneity depends not only on genetic modifications but also on non-genetic processes involving either stochastic events or epigenetic modifications making genetic biomarkers of uncertain utility. In this review, we wish to highlight how evolutionary biology can impact our understanding of carcinogenesis and resistance to therapies. We will discuss new approaches based on applied ecology and evolution dynamics that can be used to convert the cancer into a chronic disease where the drugs would control tumor growth. Finally, we will discuss the way metabolic dysfunction or phenotypic changes can help developing new delivery systems or phenotypetargeted drugs and how exploring new sources of active compounds can conduct to the development of drugs with original mechanisms of action.