KRAS Gene Mutation and Amplification Status Affects Sensitivity to Antifolate Therapy

• Patients with lung cancer and KRAS mutation responded well to antifolate therapy.
• Response linked to downregulation of KRAS expression.
• Downregulation may render cells more susceptible to chemotherapeutic drug.

CHICAGO — Testing patients with non-small cell lung cancer for both mutations and amplifications of the KRAS gene prior to therapy may help to predict response to treatment with antifolates, according to 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.

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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Founded in 1907, the American Association for Cancer Research (AACR) is the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR’s membership includes 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes seven peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of individual and team science grants in cancer research that have the potential for patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer.  

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