'Something great here'
Meanwhile, Johnson and Jänne, who had treated some DFCI lung cancer patients with Iressa, were following up other leads. While at the National Cancer Institute, Johnson had studied NSCLC tumor development in the laboratory.
A mutation, or genetic change, labeled L858R creates a target for the new drug Iressa to attack lung cancer cells. This computer image shows the kinase portion of the EGFR protein, which is abnormal in lung and some other cancers.
(Courtesy of Guillermo Paez, PhD, of the Kinase Project)
"We had cell lines from women and men, smokers and nonsmokers," he says."We found one line that was exquisitely sensitive to Iressa." So sensitive, in fact, that doses 50 times smaller than the standard halted the cancer cells' growth. With increasing evidence pointing to mutation, Johnson and Jänne sent the DNA from the highly susceptible cancer cell line to be sequenced. Meanwhile, in a parallel experiment, Jänne was collecting tissue specimens for DNA sequencing from Iressa responders and non-responders treated at Dana-Farber.
In early 2004, the paths of discovery rapidly began to converge. On a Wednesday in late March, Meyerson met with Johnson's group to report on the L858R mutations found in the Japanese patients. Johnson had just gotten the results from DNA sequencing of the Iressa-sensitive cell line.
"Matt was presenting his data, and he knew about the L858R mutation," recalls Johnson. "We said, 'It's the same mutation that's in our cell lines!' It was quite a moment."
Around this time, the final puzzle piece fell into place. Jänne telephoned Meyerson to report that the L858R mutation had also been detected in the Iressa-sensitive tumors from Dana-Farber patients, but not in the non-responders. The case was now closed: the mutation had been found in the cell lines, the Iressa responders at DFCI , and in the nonsmoking female NSCLC patients in Japan.
"The light bulb went on," says Jänne ."I said to Matthew, 'We've found something great here.'"
It is, of course, the patients who are the beneficiaries. EGFR mutation testing is now being offered at Brigham and Women's Hospital and MGH, although decisions about whether it will be designated for all NSCLC patients, or just those fitting the profile of Iressa responders, have yet to be made.
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