Introduction

Ask most oncologists when the targeted era in cancer chemotherapeutics began and it is likely they will point to a time 12 to 15 years ago when the possibility of using imatinib to target BCR–ABL in CML came into focus (1). But one could argue that the use of methotrexate and vincristine in the 1950s were the actual start of the targeted era, since both drugs are actually more specific than imatinib, having as their exclusive or primary targets dihydrofolate reductase (DHFR) and β-tubulin, respectively (2,3).

Not unlike the 1950s and the early 1980s, when oncologists felt confident that chemotherapy and then combination therapy would cure cancer, the emergence of imatinib ushered in yet another era when the demise of cancer seemed but a drug or a combination away (4). In all of these times, the recognition, and in the 1980s the knowledge, that drug resistance presented an obstacle was acknowledged, but viewed as surmountable. In the 1950s the hope was that new and more effective therapies would emerge and in the 1980s that combinations would prevail. But time and refractory cancers changed that view. Similarly, in the past decade, the fervor surrounding “targeted therapies” as the paradigm to overcome resistance is giving way to the realization that drug resistance is unfortunately the problem that will not go away (5–15).