Cancer Drug Resistance: Targets and Therapies

Abstract

Hundred years ago, Paul Ehrlich, the founder of chemotherapy, received the Nobel Price for Physiology or Medicine for his landmark immunological insights. Ehrlich postulated the existence of specific receptors (either associated with cells or distributed in the blood stream),whichmaybe regarded as side chains that bind antigens (“side-chain theory of immunity, ” see timeline in Fig. 1) [1]. According to him, each type of receptors is attuned to one special group of drugs [2]. He declared “wir m€ ussen zielen lernen, chemisch zielen lernen” (“we have to learn how to target chemically”)—Ehrlich already suspected that the key for synthetic chemistry was to modify some starting material in various ways. After the discovery of the antisyphilitic activity of Salvarsan—an organic arsenic compound—in 1908 in Paul Ehrlich’s laboratory, lead optimization led to the improved derivative Neosalvarsan in 1912. Biological activity of a lead compound for the first time was optimized through systematic modifications. This was the real beginning of chemotherapy [3,4]. It took some time—until the end of the World War II—that chemotherapy was introduced in clinical practice for cancer treatment. Gilman and coworkers treated a patient with non-Hodgkin lymphoma with nitrogen mustard, a chemical warfare agent that accidentally had caused lymphoid and myeloid suppression in humans duringWorldWar II. The therapy initially caused a dramatic antitumor effect, but by the time the third treatmentwas given, the tumor no longer responded to the chemotherapeutic treatment [4,5]. Since these early days of cancer chemotherapy, the increased knowledge of the cancer genome and the development of new drug discovery technologies, such as quantitative structure–activity relationships (QSAR), highthroughput screening (HTS), nuclearmagnetic resonance (NMR), X-ray diffraction, and protein–ligand cocrystallography, have paved the way for targeted andmultitargeted cancer therapeutics. Nevertheless, classical (unspecific cytotoxic) as well as targeted chemotherapy are often faced with one major obstacle that limits its success: drug resistance (tolerance).