Terminal Ballistics of Kinase Inhibitors: There Are No Magic Bullets

Terminal ballistics is the study of the motion and consequent effects of projectiles, especially bullets, as they interact with their intended targets. How ammunition behaves once it enters and (sometimes) exits the body is crucial information for emergency physicians and trauma surgeons for optimal management of gunshot wounds (1). Since the “founder of chemotherapy,” Paul Ehrlich, described a drug that would eliminate disease precisely and efficiently as a “magic bullet,” oncologists have been prone to militaristic metaphors (2). For optimal care of patients with cancer, it has become increasingly important for oncologists and their internal medicine colleagues to study the terminal ballistics of the newest class of anticancer agents, kinase inhibitors.

Three agents recently approved by the U.S. Food and Drug Administration (FDA), imatinib, sunitinib, and sorafenib, illustrate this point. Imatinib, the first FDA-approved kinase inhibitor (approved in 2001 for chronic myelogenous leukemia), has been hailed as a potential “magic bullet” because of its apparent selectivity for a cancer-specific target, the leukemogenic oncogene Bcr-Abl (3). Researchers subsequently recognized that imatinib had additional clinically relevant targets, including the receptor protein c-Kit, the inhibition of which makes the drug active in gastrointestinal stromal tumors. Sunitinib was developed to inhibit the vascular endothelial growth factor (VEGF) receptor-2. The FDA approved it in January 2006 for the treatment of advanced renal cell carcinoma. The drug also inhibits c-Kit and therefore has demonstrated activity in gastrointestinal stromal tumors, an effect that led the FDA to also approve sunitinib for patients with gastrointestinal …