Epidermal growth factor receptor tyrosine kinase inhibitors cultivate an aura of mystery these days.
AstraZeneca plc's Iressa (gefitinib) and OSI Pharmaceuticals Inc. and Genentech Inc.'s Tarceva (erlotinib) both are approved as treatments for refractory non-small-cell lung cancer. However, Iressa's recent failure to show a survival benefit vs. placebo - as compared to Tarceva's survival benefit of roughly 40 percent - besides questioning Iressa's future, shows just how much remains to be learned about both drugs, as well as EGFR inhibitors, in general. (See BioWorld Today, Dec. 20, 2004.)
Several new studies report on mutations found in the EGFR gene. A paper published in the March 2, 2005, issue of the Journal of the National Cancer Institute is about mutations that make tumors sensitive to treatment with EGFR tyrosine kinase inhibitors in the first place. It identifies a mutation, the first of its kind described, occurring in lung cancer patients who have never smoked.
In that paper, researchers at University of Texas in Dallas and Houston; the Fred Hutchinson Cancer Research Center in Seattle; Chiba University in Japan; Prince Charles Hospital in Brisbane, Australia; Chung Shan Medical University in Taichung, Taiwan; and Okayama University in Japan, analyzed tissue samples from primary tumors of slightly more than 500 patients. The origin of the patients was as diverse as those of the researchers; they hailed from the U.S., Australia, Japan and Taiwan. Samples from the U.S. included patients of European, East Asian, Latino and African ancestry, while those from Australia included persons of European and East Asian ancestry.
The scientists compared the tumor tissue to samples of both nonmalignant lung tissue from the same patient samples, and other cancer tissues from a different set of patients. They investigated exons 18-21 of the EGFR tyrosine kinase domain. Ninety-five percent of the mutations they identified could be classified into three different types. Each of the three types was around the ATP-binding site, which, as it happens, also is the binding site of EGFR tyrosine kinase inhibitors.
Mutations in the EGFR gene were more common in females, in persons who had never smoked, and in those of Asian ancestry (regardless of their current place of residence); those are exactly the groups that most likely are to respond to Iressa or Tarceva, both of which have about a 10 percent response rate overall. They also found that mutations in the KRAS gene, another gene in the EGFR signaling pathway, were found in 8 percent of lung cancers, but in none with the EGFR mutation. That mutation was more common in males, Caucasians, and current or former smokers.
The scientists interpreted their findings to support the idea that there are two distinct molecular pathways whose malfunction can lead to the development of lung cancer. The pathway in smokers involves KRAS gene mutations, while the pathway in people who never smoked involves EGFR gene mutations.
They also noted their findings might suggest that "exposure to carcinogens in environmental tobacco smoke may not be the major pathogenic factor involved in the origin of lung cancers in never smokers," since one would expect smoke to cause or interact with the same mutation in nonsmokers as in smokers.
When Diversity Is Bad For You
The other two papers reported on mutations that, from a patient's standpoint, are considerably less advantageous.
As described above, tumors are responsive to EGFR tyrosine kinase inhibitors due to so-called activating mutations in the EGFR gene, which somehow makes them sensitive to treatment in the first place. However, as with Gleevec (imatinib), a BCR-ABL kinase inhibitor, most patients ultimately acquire further mutations that make them resistant to treatment. In the March 2005 issue of the open-access journal PLoS Medicine, scientists from Memorial Sloan-Kettering Cancer Center showed that in three out of six relapsed patients they studied, such resistance was due to the replacement of a serine by a threonine in position 790 of the tyrosine kinase (a so-called T790M mutation).
Structural analysis suggested that another compound, lapatinib, might be effective against the mutated tyrosine kinase; lapatinib is being developed by GlaxoSmithKline plc for the treatment of refractory metastatic breast cancer, but has not been tested against lung cancer. A separate case study showing the same mutation in a single patient was published in the Feb. 24, 2005, issue of the New England Journal of Medicine.
Given that half of the samples studied in the PLoS Medicine article harbored neither the T790M mutation nor a mutation in the KRAS gene, there clearly are manifold resistance mechanisms (again, similar to Gleevec resistance, where more than a dozen different mutations have been described to date).
In an accompanying commentary in PLoS Medicine, scientists from Harvard Medical School, the Dana-Farber Cancer Institute and the University of Leuven in Belgium pointed out that "as might have been anticipated in treatment of cancer with any single agent, resistance to small-molecule tyrosine kinase inhibitors has emerged as a significant clinical problem." But they also noted that three years after the original description of acquired Gleevec resistance "new drugs are now in clinical trials that are potent inhibitors of imatinib-resistant BCR-ABL mutants."
Presumably, the same strategy will be possible in treating Iressa- and Tarceva-resistant mutations of the EGFR tyrosine kinase.