Lasker~DeBakey
Clinical Medical Research Award

Acceptance remarks by Charles Sawyers

It is a humbling and unexpected honor to be here accepting the Lasker-DeBakey Clinical Research Award. Brian Druker and I met nearly 20 years ago when we were both postdoctoral fellows studying the signaling properties of the BCR-ABL enzyme. Brian was in Boston, I was in Los Angeles. I met Nick Lydon a few years later in Basel, Switzerland when he and Brian invited me to join the effort to move the compound that would become Gleevec into the clinic. Successful partnerships are born in unpredictable ways. Who knew what would follow?

Among our trio, I am known primarily as the resistance guy. In 2001 my group discovered that patients who relapse while taking Gleevec have mutations in the BCR-ABL enzyme that prevent the drug from binding its target. This was a big surprise because all bets were on another explanation - that tumors would escape their need for BCR-ABL because they had so many other genetic mutations that could presumably drive the growth of the tumor. Instead, the answer was elegantly simple. The tumor does everything in its power to maintain BCR-ABL activity. In hindsight, this was clear evidence of a general principle we now call oncogene addiction that guides much of cancer drug development today.

Many people played a role in the remarkable convergence of events that allowed us to move so quickly from discovering the cause of resistance in 2001 to a solution to overcome it just a few years later. Pasteur said that "chance favors the prepared mind." I credit Owen Witte, my postdoctoral mentor, for "preparing" my mind to connect the various pieces of the resistance puzzle that we faced first in the clinic, then in the laboratory. Mercedes Gorre and Neil Shah, who are both here today, conducted the experiments in my lab that led to the discovery of the resistance mutations and courageously persevered when their initial results were challenged. John Kuriyan solved the structure of Gleevec bound to ABL, then partnered with us to understand how the many different mutations we were finding in patients confer resistance. Only through that collaboration did we come to the hypothesis that an inhibitor that binds BCR-ABL differently might offer a common solution against the many different Gleevec-resistant mutations. In an amazing coincidence, Frank Lee and Rob Kramer at Bristol Myers Squibb had a compound with precisely the properties we were imagining but that they had originally discovered for a different purpose. Four years later that compound, dasatinib or Sprycel, was approved by the FDA for Gleevec-resistant chronic myeloid leukemia.

In closing, I thank the patients who participated in these clinical trials, many of whom have sent me messages of joy ever since the Lasker announcement. I also thank my parents, my brother and sister, and my wife and children, all here today, for supporting my dedication to this work.