When good cancer drugs go bad - or rather, ineffective - the most common reason is a second mutation in the original target. Gleevec (imatinib, Novartis Inc.) is the best-known example. Secondary mutations in the bcr-abl kinase that is hyperactive in chronic myelogenous leukemia, and targeted by Gleevec, lead to a relapse rate of 17 percent over five years. For Gleevec, most of the fight against resistance has focused on developing drugs that remain active against bcr-abl kinases with secondary mutations. (See BioWorld Today, Dec. 12, 2006.)
But a paper in the April 26, 2007 issue of Sciencexpress shows that resistance to kinase inhibitors also can develop in another way: by mutations in a second kinase that ultimately activates the same uncontrolled growth pathways.
The study focused on resistance mechanisms to Tarceva (erlotinib, Genentech Inc. and OSI Pharmaceuticals Inc.) and Iressa (gefitinib, AstraZeneca plc,) which inhibit the epidermal growth factor receptor kinase and are approved for the treatment of non-small-cell lung cancer.
Senior author Pasi Jänne, an assistant professor of medicine at Harvard Medical School, described the difference between such resistance and that seen to Gleevec to BioWorld Today. "The unique aspect of Met amplification as a resistance mechanism is that Iressa and Tarceva are not Met inhibitors and Met is not a downstream signaling pathway of EGFR," he said.
Jänne and his team wanted to study how resistance developed. The scientists induced resistance in a cultured lung cancer cell line by exposing it to Iressa, and then tested its molecular mechanisms.
They found that while half of all cases of drug resistance were due to secondary mutations in the EGFR kinase; another 20 percent of resistance was caused by a change in MET kinase, which roughly 30 percent of resistance cases still are unaccounted for.
The path from EGFR kinase mutations to cancer proceeds via the activation of the molecule Erbb3, and Jänne said that "in order for Iressa and Tarceva to be effective, Erbb3 absolutely has to be turned off." Further studies showed that Met kinase also activated Erbb3 and its pathway. Jänne described the EGFR and Met kinases as "two inputs that are feeding into the same pathway." Treatment with a combination of Iressa and a Met kinase inhibitor once again stopped the growth of the resistant tumor cells in its tracks.
Jänne said his results have implications for the clinic as well as basic research. "When a tumor becomes resistant to Iressa or Tarceva, it will be incredibly important to figure out why," he told BioWorld Today. Jänne noted that most patients who develop resistance currently do not undergo secondary biopsies to check on the underlying molecular mechanism.
Another basic question is the scope of Met kinase in cancer. San Francisco-based biotech Exelixis Inc., among others, is in the clinic with Met kinase inhibitors. The company is in Phase II trials with XL880, which inhibits Met and VEGFR2, for the treatment of gastric cancer, and in Phase I for the treatment of advanced solid tumors.
Met kinase had been implicated in other tumor types, including non-small-cell lung cancer, before, but Jänne said his team's findings are the first to specifically finger Met kinase as important in resistance. It currently is unclear whether amplification of the Met kinase serves as a more general resistance mechanism in cancer. "That's what we'd like to determine over the next few months," Jänne said.