Proefschrift

CHAPTER 1. INTRODUCTION MTD strongly selects for already present resistant cell type by eliminating potential sensitive competitors and by enforcing strong selection pressures for evolution of novel resistance mechanisms during treatment. This has been explicitly shown in-vivo by serial biopsy and by extracting circulating tumor cells showing absence and subsequent presence of mutations conferring resistance to therapy (Figure 1.3) (Gatenby and Brown, 2018; Arena et al., 2015; Navin et al., 2011; Diaz Jr et al., 2012). Figure 1.3: Emergence of Multiple Epidermal Growth Factor Receptor Extracellular Mutations during Cetuximab Treatment in Colorectal Cancer. Reprinted from Arena et al. (2015) with permission from AACR. 1.4 A Similar “Resistance Crisis” What is a practical course of action assuming that current and presumably future developed drugs will fail to provide cure due to evolution of resistance? Here we look to agricultural pest management where a similar resistance crisis, literally referred to as “the dark ages,” occurred in the late 20th century (Peshin and Dhawan, 2009). Similar to using MTD in cancer therapy in an attempt to eradicate all cancerous cells, the agriculture industry used high concentrations of synthetic pesticides in an attempt to eradicate major pests. Most notably, DDT (dichloro-diphenyl-trichloroethane) was first discovered in 1874 and first used as an insecticide beginning in 1938. In 1947, a mere 9 years later, the first cases of DDT resistance were reported in mosquitoes (Brown, 1986). By 1953 the diamondback moth became the first crop pest in the world to develop resistance to DDT and by the late 1980’s had developed resistance to practically all synthetic insecticides (Talekar and Shelton, 1993). Interestingly, in 1917, the diamondback moth was said to be “so effectively held in repression by parasites that it rarely becomes more than a minor pest” (Marsh, 1917). The increased use of synthetic insecticides caused a two-fold loss of control. Firstly, the 8