Treatment for chronic myelogenous leukemia: the long road to imatinib

Abstract

The scientists of today have become accustomed to the extremely rapid pace of progress in the biomedical sciences spurred on by the discovery of recombinant DNA and the advent of automated DNA sequencing and PCR, with progress usually being measured in months or years at most. What is often forgotten, however, are the many prior advances that were needed to reach our present state of knowledge. Here I illustrate this by discussing the scientific discoveries made over the course of the past century and a half that ultimately led to the recent successful development of drugs, particularly imatinib mesylate, to treat chronic myelogenous leukemia.

Figure 1. A timeline of the different avenues of research endeavor that came together and led to the successful development of imatinib as a treatment for CML.

Most of these disparate research efforts were started through a desire to understand the mechanisms underlying cancer and to ultimately develop therapies. A significant acceleration in progress came in the 1970s with Nixon’s “war on cancer,” which brought a lot of new people and ideas into the cancer field. The advent of molecular cloning and DNA sequencing in the mid-1970s also played a critical role, allowing for the identification of oncogenes and their products. gof, gain-of-function; HZ4-FeSV, Hardy-Zuckerman 4 feline sarcoma virus; mT, middle T antigen; NEJM, New England Journal of Medicine; Ph chr, Philadelphia chromosome; PK, protein kinase; TK, tyrosine kinase; TKI, tyrosine kinase inhibitor.

Figure 2. c-Src and c-Abl have similar negative regulatory mechanisms.

Figure modified with permission from Cell (40). C, C terminus; N, N terminus; pY, phosphorylated tyrosine.

Figure 3. Structures of Src and Abl family tyrosine kinases and BCR-ABL.

Figure modified with permission from Nature Reviews Molecular Cell Biology (113).