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Strategies Target Resistance to EGFR Therapy in Lung Cancer

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Strategies Target Resistance to EGFR Therapy in Lung Cancer

CORONADO, Calif. (EGMN) - The advent of epidermal growth factor receptor inhibitors to treat EGFR-mutant lung cancer has been a "wonderful success," said Dr. Jeffrey Engelman of Massachusetts General Hospital Cancer Center in Boston. But the duration of response averages only about 10 months, and patients having these tumors tend to be younger.

"Telling a 40-year-old that you can give him a progression-free survival of 15 months, although exciting to us from a historical perspective, is obviously not really satisfactory to patients," he told an audience of lung cancer researchers and clinicians at a joint conference of the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

"Clearly, these cancers are evolving, and they are able to become resistant to these therapies, and we somehow need to deal with the fact that these drugs (and others) are not working for longer," he advised.

If Dr. Engelman's words cast a cloud, he also offered a glimpse of how resistance might be overcome. New molecular and physiologic insights are revealing ways of improving on lung cancer therapies that target EGFR, he reported.

EGFR inhibitors such as erlotinib (Tarceva) and gefitinib (Iressa) induce cell death by preventing downstream signalingin the PI3 kinase, MAP kinase, and other pathways, he explained. Over time, cancers can acquire resistance to these agents by two main mechanisms. They may develop a second mutation in the EGFR gene (e.g., the T790M mutation), or they can develop new ways of activating the downstream pathways. For example, amplification of the proto-oncogene MET or activation of the insulin-like growth factor-1 receptor (IGF-1R) can restore signaling.

Resistance due to the T790M mutation could be overcome with an irreversible EGFR inhibitor, according to Dr. Engelman. Two such agents have been disappointing with limited efficacy and dose-limiting toxicity in clinical trials, however. A new irreversible EGFR inhibitor in preclinical testing is showing a better profile.

Combined treatment with a MET inhibitor and an EGFR inhibitor could overcome resistance due to MET amplification, he continued. "This is a highly effective therapy in the right patient," he commented. "But the problem is that most patients who become resistant don't have this mechanism." Similarly, resistance due to IGF-1R activation could be overcome by combined treatment targeting both IGF-1R and EGFR.

Going forward, three strategies are being investigated to improve EGFR therapy, according to Dr. Engelman.

"One obvious idea is to use these combinations up front, to prevent the acquisition of resistance," he said. "Hopefully, by killing the cancer and some of these resistant cells, you'll get longer times to progression and maybe even some cures." Unfortunately, combination therapy is proving too toxic to be used widely.

A second strategy is to analyze pretreatment tumor specimens to determine how patients will become resistant and tailor treatment accordingly. For example, an analysis by his laboratory of EGFR-mutant tumors from patients that became resistant to EGFR inhibitors found that MET amplification was detectable before treatment in all of four tumors developing MET-dependent resistance, compared with only one of nine that developed MET-independent resistance.

A third strategy would target multiple resistance mechanisms simultaneously. "The defining step [in resistance], the one pathway that is always activated, is PI3 kinase signaling," Dr. Engelman pointed out, tracing the roots of this approach.

An investigational drug from Novartis called BEZ235 inhibits PI3 kinase. It has been ineffective, however, when used alone to treat lung tumors resistant to EGFR inhibitors in preclinical studies (Proc. Natl. Acad. Sci. U.S.A. 2009;106:19503-8). But when another investigational drug called AZD6244 from AstraZeneca is added, the combination induces marked tumor regression. AZD6244 inhibits signaling in the MAP kinase pathway.

"There is a reason to try to inhibit PI3 kinase and MAP kinase besides the fact that they both have their own pathways regulating growth and survival," he said. "They actually have very important points of convergence, especially among the apoptotic proteins."

From a larger perspective, "I think this issue of resistance is going to follow each story of a successful targeted therapy," Dr. Engelman predicted. Hence, these key lessons being learned about overcoming resistance to EGFR inhibitors in lung cancer will likely inform future efforts on other targeted therapies as well.

Dr. Engelman disclosed that he has a patent regarding strategies to overcome resistance to EGFR inhibitors.

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