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Shifting paradigms: the seeds of oncogene addiction

Nature Medicine volume 15, pages 1158–1161 (2009)Cite this article

Thomas Kuhn's The Structure of Scientific Revolutions argues that new insights often come from scientific renegades who champion new paradigms to account for observations that cannot be adequately explained by existing theory1. His views intrigued me while I was a Princeton undergraduate interested in the history of science. Imagine the scientific upheaval in 1543 when Copernicus proposed a heliocentric model to explain various astronomical observations, challenging the geocentric view of Ptolemy that had been in place for centuries. Cancer biologists and physicians completing their training today are likely to assume that the imatinib story—the discovery that imatinib (Gleevec) is an effective treatment for chronic myeloid leukemia (CML)—is a logical extension of earlier landmark discoveries that CML is caused by BCR-ABL, the tyrosine kinase inhibited by imatinib. Although true in a broad sense, the backstory is not quite so simple.

In 1995, the year that imatinib was first described by Nick Lydon and his colleagues, the general consensus was that cancers such as CML could be initiated by single oncogenic events or driver mutations. But there was skepticism about whether such tumors would remain dependent on the initial lesion, owing to the innumerable additional oncogenic events that accumulate in most cancers. This widely held view had important implications, because it predicted that inhibitors targeting the initiating lesion would fail unless a cocktail of drugs could be developed to target multiple lesions. Just 14 years later, this conclusion has been turned on its head. Most cancer drug discovery efforts are now focused on targeting individual oncogenic lesions, in the belief that many cancers remain dependent on driver mutations. Although the success of imatinib was not a revolution in the Copernican sense, it spawned a transformation in cancer research that has fueled an urgency to characterize cancer genomes comprehensively and discover the driver mutations in all cancers.

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Figure 1: Driver mutations in chronic phase versus blast crisis.
Figure 2: Original sequence trace revealing the T315I mutation.
Figure 3: ABL kinase domain structure bound to imatinib, with locations of 13 resistance mutations indicated.
Figure 4: Individuals who participated in the phase 1 clinical trial of imatinib at UCLA.

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Acknowledgements

Without the discovery of imatinib by N. Lydon and the demonstration of its preclinical activity by B. Druker, none of the work described here would have been possible. I am forever grateful to Brian and Nick for inviting me to join them on this project. I am indebted to O. Witte for accepting me into his laboratory when I was a naive oncology fellow and training me to think like a scientist. There could be no better mentor for an aspiring physician-scientist. I thank M. Talpaz for teaching me the intricacies of CML and for a wonderful partnership in the clinical development of imatinib and dasatinib. I am especially grateful for the hard work and dedication of the many graduate students, postdoctoral trainees and technicians who have been a part of my group over the past 16 years—you are my second family. I especially want to single out M. Gorre and N. Shah, who broke the resistance story and worked essentially 24-7 for much of 2001–2002 to be sure we had it right and to follow up on the implications for next-generation inhibitors. It is hard to envision a more invigorating time in the laboratory, where the results of each experiment made a difference. The insights that led us to dasatinib would never have been possible without J. Kuriyan, who showed me the power of structural biology (with a front-row seat and three-dimensional glasses at his lab group meetings). I still owe John a beer for the figure he made in 2001 showing steric hindrance caused by the T315I mutation, but I suspect my obligation has now grown to a case of champagne. The dasatinib story emerged from a wonderful collaboration on the preclinical work with F. Lee and R. Kramer at Bristol-Myers Squibb, then on the clinical development with A. DeCillis, C. Nicaise and R. Canetta. One of the unique aspects of life as a physician-scientist is the opportunity to care for patients who, in effect, are the laboratory for your translational ideas. I had the privilege to care for several hundred patients with CML from 1998 to 2006, all of whom volunteered their lives to allow us to test our hypotheses. Many patients from the very early trials are no longer with us, but many others still are. I thank all of them and their families for their courage and inspiration. The clinical trials of imatinib and dasatinib were conducted in record time, requiring an amazing team of individuals working together to handle the volume of patients and clinical data collected. I especially want to thank my UCLA colleagues R. Paquette, L. Haddad, G. Naessig, D. Slamon and J. Gasson for all their support during the two-year period from 2000 to 2001 that none of us will ever forget. Lastly, I thank my family for all their support, encouragement and understanding. My parents, John and Julia Sawyers, both physicians, have been my role models from the beginning. My children, Sophie and Sam, amaze me every day with their sense of adventure and curiosity about everything in life. My wife, Susan, has been my companion and confidant for the past 21 years. She keeps me on an even keel and smiling all day long.

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  1. Charles L. Sawyers is in the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center and Howard Hughes Medical Institute, New York, New York, USA.,

    Charles L Sawyers

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Sawyers, C. Shifting paradigms: the seeds of oncogene addiction. Nat Med 15, 1158–1161 (2009). https://doi.org/10.1038/nm1009-1158

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