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Combination targets: some drugs may work best when they work together
Date:10/24/2007

ning it with ABT-737, a small molecule drug that primes tumor cells to undergo apoptosis, or programmed cell death.

About ten percent of tumors from lung cancer patients harbor mutations in the kinase domain of the epidermal growth factor receptor (EGFR) gene, and these mutations are associated with increased sensitivity to EGFR TKIs. said Yixuan Gong, Ph.D., a post-doctoral researcher at Memorial Sloan-Kettering. EGFR TKIs, while certainly beneficial, unfortunately, do not cure patients whose tumors have these mutations, and resistance develops after long time use. Were attempting to enhance the effectiveness of EGFR TKIs by combining TKI therapy with ABT-737, a BCL-2 inhibitor.

According to Gong, mutated EGFRs produce growth signals that drive uncontrolled lung tumor cell division. Inhibition of mutated EGFR is a very effective treatment for these types of lung cancers, she says.

Gong and her colleagues at Memorial Sloan-Kettering demonstrated how lung cancer cell lines with EGFR mutations undergo apoptosis when exposed to erlotinib. In particular, they found that such cells die by a mechanism called the intrinsic apoptotic pathway. Erlotinib, the researchers say, induces dramatic changes in the pro-apoptotic protein, BIM, and this protein is required for erlotinib-triggered cell death.

The improved understanding of how EGFR mutant cells actually respond to EGFR TKIs will help us to identify strategies to enhance tumor cell death and will also help us to look for possible reasons why tumor cells persist despite treatment, Gong said.

In studies of EGFR TKI-sensitive cancer cells, the researchers found that ABT-737 significantly enhanced erlotinib-induced cell death. It is proof of principle that you can enhance tumor response to EGFR TKIs by priming tumor cells to a more deathprone state with small molecules that manipulate the intrinsic apoptotic pathway, Gong said. We hope to design clinical trials based on this st
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Contact: Greg Lester
greg.lester@aacr.org
267-646-0554
American Association for Cancer Research
Source:Eurekalert

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