Sensitivity to Antifolate Therapy Influenced by KRAS Gene Mutation and Amplification Status

by Kathy Jones on  April 12, 2012 at 6:50 PM Genetics & Stem Cells News   - G J E 4
Response to treatment with antifolates may be predicted by testing patients with non-small cell lung cancer for both mutations and amplifications of the KRAS gene prior to therapy.
 Sensitivity to Antifolate Therapy Influenced by KRAS Gene Mutation and Amplification Status
Sensitivity to Antifolate Therapy Influenced by KRAS Gene Mutation and Amplification Status

These findings are contained in the updated results of a preclinical study presented at the AACR Annual Meeting 2012, held here March 31 - April 4.

Patients, especially those with lung cancer, who have KRAS gene mutations have a worse prognosis and do not respond well to targeted therapies, according to Sarah Bacus, Ph.D., Quintiles senior vice president and chief scientific officer of translational research and development, oncology. The results suggest that although these mutations are linked to a poor response to targeted therapies, they may predict response to treatment with antifolates, as long as the number of mutant genes is not amplified.

She and her colleagues assessed the relationship between antifolate medications and KRAS mutations and amplification, where the gene has an excess number of copies.

The preliminary results of the study were presented in November at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics. Researchers treated human non-small cell lung cancer cell lines (KRAS wild type, KRAS-mutant nonamplified and KRAS-mutant amplified) with the antifolates methotrexate or pemetrexed.

In lung cancer, the KRAS-mutant tumors need the folate pathway, which is associated with the growth of cancer. Treatment with the antifolate pemetrexed led to dramatic responses in patients with KRAS-mutant lung cancer. Patients with KRAS-wild type were less responsive. The researchers found a similar trend in KRAS-mutant lung cancer cell lines. When cell lines with KRAS mutations were deprived of access to this pathway, they failed to grow. However, this response was not seen if the number of copies of the KRAS-mutant gene was amplified or if the KRAS was wild type.

"KRAS mutations are most frequently observed in pancreatic, colorectal, lung, endometrial and biliary tract cancers, and as such, antifolates may have utility in the treatment of these cancers alone or in combination with other chemotherapies such as DNA-damaging agents," Bacus said. She recommended that before prescribing an antifolate, whether in lung cancer or other cancers where KRAS mutations are prevalent, physicians should test for KRAS mutation and amplification, because the study results suggest that patients are likely to respond well only if the KRAS gene is mutated and not amplified.

Source: Eurekalert

Post your Comments

Comments should be on the topic and should not be abusive. The editorial team reserves the right to review and moderate the comments posted on the site.
User Avatar
* Your comment can be maximum of 2500 characters
Notify me when reply is posted I agree to the terms and conditions

You May Also Like

View All