Drugs Join Forces to Overcome Lung Cancer Resistance

October 30, 2009

BY: LEIGH MACMILLAN

Combining two targeted cancer therapies may overcome the resistance that some lung tumors develop during treatment, according to a recent report in the Journal of Clinical Investigation.

The study, which tested the drug combo in mouse models of lung cancer, supports moving forward with clinical trials in patients with lung cancer.

The research focused on a vexing problem: targeted therapies like Iressa and Tarceva are very effective for lung cancer patients whose tumors have certain genetic changes. But eventually, tumors grow that are resistant to the drugs.

“A lot of groups have been trying to find ways to overcome this acquired resistance,” said William Pao, M.D., Ph.D., Ingram Associate Professor of Cancer Research at the Vanderbilt-Ingram Cancer Center. Pao led the drug combination studies while he was a faculty member at Memorial Sloan-Kettering Cancer Center in New York.

William Pao, M.D., Ph.D.

William Pao, M.D., Ph.D.

Iressa and Tarceva block the activity of the epidermal growth factor (EGF) receptor — a protein that is often abnormally activated in tumors. Pao and others showed in 2004 that lung cancers with mutations in the EGF receptor were highly sensitive to these drugs.

“We know now that patients who have certain EGF receptor mutations in their tumors have a greater than 70 percent chance of having their tumors shrink with Iressa or Tarceva — they derive more benefit from these targeted therapies than they do from chemotherapy,” Pao said.

But after about a year on therapy, the tumors usually return. In about half of the now drug-resistant tumors, the culprit is a new mutation in the EGF receptor — a single change (called T790M) that prevents Iressa and Tarceva from fitting into the protein to block its activity.

A new group of EGF receptor inhibitors has shown promise in overcoming T790M-mediated resistance in cultured tumor cells, but no targeted agents have been approved for treating patients with acquired resistance to Iressa and Tarceva.

Pao and his colleagues took advantage of mouse models they generated to study the biology and treatment of lung cancer.

The mice, which express EGF receptors with mutations that match those found in human lung cancers, develop lung tumors. The tumors with Iressa/Tarceva-sensitive mutations “melt away” when the mice are treated with either of those drugs, Pao explained, but the tumors with the T790M mutation do not respond to Iressa or Tarceva and in fact grow bigger.

“They mimic what we see in patients,” Pao said, making the mice ideal for “clinical trials” that compare lung cancer treatments.

The team tested one of the newer EGF receptor inhibitors (called BIBW-2992) in the mice, but it did not shrink the T790M tumors.

To look for new targets for therapy, the researchers compared the genes expressed by the lung tumors versus normal lung tissue. They found that two EGF receptor binding proteins were more highly expressed in the lung tumors. This finding suggested that blocking the interaction of the binding proteins with the EGF receptor — using an antibody drug like Erbitux — might be an effective treatment. They tested Erbitux, but it did not shrink the lung tumors in mice with the T790M drug-resistant mutation either.

The investigators next tried a drug combination — Erbitux and BIBW-2992 — to treat the T790M tumors.

“Lo and behold, the tumors completely melted away,” Pao said. No other single agent or drug combination they tested was effective in shrinking the drug-resistant tumors.

“We think this is a promising way to overcome T790M-mediated resistance, and we’re now planning a clinical trial.”

The strategy of using drug combinations that “target in multiple ways the molecules that are driving the cancer” might be suitable for other tumors that harbor activated mutant receptors.

Pao is leading the Personalized Cancer Medicine Initiative at Vanderbilt-Ingram, an effort to routinely determine the genetic changes in tumors and select treatments that target those changes.

The National Cancer Institute supported the research.

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