Genomics

Modeling Resistance in the Laboratory

Pasi Jänne, MD, PhD, left, and Bruce Johnson, MD 

When Pasi Jänne, MD, PhD, was a fellow, the Dana-Farber/Partners clinical oncology fellowship suited him perfectly; it integrated his two major interests, science and medicine, while introducing him to distinguished mentors like Bruce Johnson, MD, of the Department of Medical Oncology. The difficult part, he found, was having to tell patients that their lung cancer had relapsed. Today, as a thoracic oncologist and clinical researcher, Jänne is bringing new hope to patients by uncovering the mechanisms of resistance in lung cancer and designing more effective therapies.

The drugs gefitinib (Iressa) and erlotinib (Tarceva), which inhibit the epidermal growth factor receptor (EGFR), initially work in patients with EGFR mutations, but then fail as the tumors become resistant to treatment. Studying exactly how this happens, however, is no easy matter, explains Jänne, because patients do not routinely undergo repeat biopsies that can be analyzed for genetic changes.

To circumvent the problem, he and colleagues modeled resistance in the laboratory, by treating EGFR-mutant cells with gefitinib and isolating those that became resistant. Investigators then compared the resistant cells to gefitinib-sensitive cells, deploying three different techniques: genome-wide copy number analysis (using the high-density SNP arrays adapted by Dana-Farber colleague Matthew Meyerson, MD, PhD), RNA expression profiling and proteomic analysis. "All three independent approaches pointed us in the same direction," says Jänne, recalling the excitement of an entirely unexpected discovery - amplification of the MET kinase gene, which provided an alternate pathway for tumor growth.

Within a year, he had begun enrolling patients in a multicenter clinical trial combining Tarceva with a MET inhibitor. "We were hopeful of finding something new for patients," he says, "and we did!"