Patients with non-small cell lung cancer who have mutations in the KRAS gene, a GTPase and early player in many signal transduction pathways, should respond well to the antifolate class of drugs, according to results of a recent study comparing human lung cancer cell lines and patients conducted by Quintiles, a clinical research organization and consulting service company for the pharmaceutical and biotechnology industries.

?Our findings indicate that when patients with lung cancer have specific changes in the KRAS gene, they become very amenable to antifolate drugs,? said lead researcher Sarah Bacus, Ph.D., Quintiles senior vice president and chief scientific officer of translational research and development, oncology. ?This treatment stops the KRAS gene from being expressed in cancer cells and they die because they depend on this gene.?

Bacus presented the study results at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, held November 12-16, 2011, in the Moscone Center West, San Francisco, CA.

Limited treatment options
KRAS mutant non-small cell lung cancer (NSCLC) is an ?aggressive form of cancer,? Bacus said. ?Until today, there have been limited treatment options available for those patients.? Bacus and colleagues treated human NSCLC cell lines (KRAS wild type, KRAS mutant nonamplified and KRAS mutant amplified) with the antifolates methotrexate (MTX), formerly known as amethopterin or pemetrexed (Alimta?, Eli Lilly and Company), an anticancer drug known as an antimetabolite approved for the treatment of advanced or metastic nonsquamous non- small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM).

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Potent downregulation of KRAS gene
Results showed that KRAS wild-type and KRAS mutant amplified cells were relatively resistant to antifolate treatment. In contrast, antifolates inhibited growth in KRAS mutant nonamplified cell lines. The researchers also discovered a potent downregulation of KRAS gene expression in treated cells. Bacus reported dramatic and prolonged responses to pemetrexed therapy in patients with KRAS mutant NSCLC.

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Mutations
Bacus recommended that oncologists treating lung cancer patients order two tests. One test designed to look for the KRAS mutation and the other test to measure KRAS amplification. ?Looking at the cancer mutations is not enough; you have to look at gene copies,? Bacus said. ?It is important before administering very expensive drugs to make sure that those mutations appear.?

This study was funded by the Quintiles Translational Research and Development Group. No external funding was used to finance the research.

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