Treatment-Induced Mutagenesis and Selective Pressures Sculpt Cancer Evolution

Despite the great progress in our understanding of the molecular basis of human cancer, the heterogeneity of individual tumors and the evolutionary pressures imposed by therapy have hampered our ability to effectively eradicate and control this disease. How, therefore, do cancers evolve under the selective pressures of cancer therapy? Recent studies have linked both primary (or de novo) and acquired treatment resistance to intratumor heterogeneity and clonal evolution. Resistance to targeted therapies often includes mutation of the drug target itself and aberrations of pathways upstream of, downstream from, or parallel to the drug target. For systemic chemotherapies, discrete and recurrent resistance-conferring genetic aberrations have eluded the community, due in part to their wide-ranging mutagenic effects. In this review, we discuss different patterns of clonal evolution during treatment-specific selective pressures and focus on the genetic mechanisms of treatment resistance that have emerged to both targeted therapies and chemotherapies.