KRAS gene mutation and amplification status affects sensitivity to antifolate therapy

Public release date: 4-Apr-2012
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Contact: Jeremy Moore
Jeremy.Moore@aacr.org
215-446-7109
American Association for Cancer Research

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.

Press registration for the AACR Annual Meeting 2012 is free to qualified journalists and public information officers: http://www.aacr.org/PressRegistration.

Follow the AACR on Twitter: @aacr #aacr

Follow the AACR on Facebook: http://www.facebook.com/aacr.org

About the AACR

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 policy makers about the value of cancer research and related biomedical science in saving lives from cancer.

For more information about the AACR, visit http://www.AACR.org.

Presenter: Sarah Bacus, Ph.D.

Abstract Number: LB-449

Title: KRAS mutation and amplification status predicts sensitivity to antifolate therapies in Non Small Cell Lung Cancer

Author Block: Diarmuid M. Moran, Patricia Trusk, Scott A. Shell, D. Ross Camidge, Robert C. Doebele, Eamon Berge, Mark Vincent, Sarah Bacus. Quintiles Transnational Corp., Westmont, IL, University of Colorado, Denver, CO, University of Western Ontario, London, ON, Canada.

Abstract: Somatic genetic mutation in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene has been linked to poor prognosis and resistance to various targeted therapeutics in Non Small Cell Lung Cancer (NSCLC). Therapeutic strategies that target tumors harboring these mutations represent an unmet medical need. In this study, we investigated the relationship between antifolate sensitivity and KRAS mutation/amplification status in NSCLC.

Human NSCLC cell lines (KRAS wild type, KRAS mutant non-amplified and KRAS mutant amplified) were treated with Methotrexate (MTX) or Pemetrexed (PEM) and assayed for proliferation. In these studies, KRASwt (wildtype) and KRASmut (mutant) amplified cells showed resistance to MTX treatment (IC50 >10?M). In contrast, growth of all KRASmut non-amplified cell lines studied was inhibited with MTX treatment (IC50 Collectively, these studies identify higher sensitivity to antifolates in KRASmut non-amp NSCLC cell lines. Antifolate therapies decrease KRAS gene expression in KRASwt and KRASmut but do not do so in KRASmut amplified cells. We propose that decreased KRAS gene expression is detrimental to KRASmut cells due to their dependency on this survival pathway. We also propose that decreases in KRAS gene expression are mechanistically linked to stress (folate inhibition) induced miRNA expression which target KRAS gene expression. Overall, antifolates represent a novel method to target KRAS and as such should be investigated further for use in this subtype of NSCLC. As clinical evidence emerges, both KRAS mutation and amplification status should be incorporated for patient stratification prior to antifolate treatment.

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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.

Public release date: 4-Apr-2012
[ | E-mail | Share ]

Contact: Jeremy Moore
Jeremy.Moore@aacr.org
215-446-7109
American Association for Cancer Research

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.

Press registration for the AACR Annual Meeting 2012 is free to qualified journalists and public information officers: http://www.aacr.org/PressRegistration.

Follow the AACR on Twitter: @aacr #aacr

Follow the AACR on Facebook: http://www.facebook.com/aacr.org

About the AACR

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 policy makers about the value of cancer research and related biomedical science in saving lives from cancer.

For more information about the AACR, visit http://www.AACR.org.

Presenter: Sarah Bacus, Ph.D.

Abstract Number: LB-449

Title: KRAS mutation and amplification status predicts sensitivity to antifolate therapies in Non Small Cell Lung Cancer

Author Block: Diarmuid M. Moran, Patricia Trusk, Scott A. Shell, D. Ross Camidge, Robert C. Doebele, Eamon Berge, Mark Vincent, Sarah Bacus. Quintiles Transnational Corp., Westmont, IL, University of Colorado, Denver, CO, University of Western Ontario, London, ON, Canada.

Abstract: Somatic genetic mutation in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene has been linked to poor prognosis and resistance to various targeted therapeutics in Non Small Cell Lung Cancer (NSCLC). Therapeutic strategies that target tumors harboring these mutations represent an unmet medical need. In this study, we investigated the relationship between antifolate sensitivity and KRAS mutation/amplification status in NSCLC.

Human NSCLC cell lines (KRAS wild type, KRAS mutant non-amplified and KRAS mutant amplified) were treated with Methotrexate (MTX) or Pemetrexed (PEM) and assayed for proliferation. In these studies, KRASwt (wildtype) and KRASmut (mutant) amplified cells showed resistance to MTX treatment (IC50 >10?M). In contrast, growth of all KRASmut non-amplified cell lines studied was inhibited with MTX treatment (IC50 Collectively, these studies identify higher sensitivity to antifolates in KRASmut non-amp NSCLC cell lines. Antifolate therapies decrease KRAS gene expression in KRASwt and KRASmut but do not do so in KRASmut amplified cells. We propose that decreased KRAS gene expression is detrimental to KRASmut cells due to their dependency on this survival pathway. We also propose that decreases in KRAS gene expression are mechanistically linked to stress (folate inhibition) induced miRNA expression which target KRAS gene expression. Overall, antifolates represent a novel method to target KRAS and as such should be investigated further for use in this subtype of NSCLC. As clinical evidence emerges, both KRAS mutation and amplification status should be incorporated for patient stratification prior to antifolate treatment.

---

[ | E-mail | Share ]

?

AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.

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