KRAS mutations and outcomes for patients with stage IV NSCLC treated with frontline platinum/pemetrexed based chemotherapy.

Levy, Benjamin; Seetharamu, Nagashree; Richardson, Stacie; Becker, Daniel; Choi, Walter; Evans, Andrew; Bhora, Faiz Y.; Connery, Cliff P.; Grossbard, Michael L.; Chachoua, Abraham

doi:10.1200/jco.2012.30.15_suppl.e18139

Cited by 4 publications

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KRAS-Mutant Lung Cancers in the Era of Targeted Therapy

Naidoo

Drilon

2015

Advances in Experimental Medicine and Biology

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KRAS-mutant lung cancers account for approximately 25% of non-small cell lung carcinomas, thus representing an enormous burden of cancer worldwide. KRAS mutations are clear drivers of tumor growth and are characterized by a complex biology involving the interaction between mutant KRAS, various growth factor pathways, and tumor suppressor genes. While KRAS mutations are classically associated with a significant smoking history, they are also identified in a substantial proportion of never-smokers. These mutations are found largely in lung adenocarcinomas with solid growth patterns and tumor-infiltrating lymphocytes. A variety of tools are available for diagnosis including Sanger sequencing, multiplex mutational hotspot profiling, and next-generation sequencing. The prognostic and predictive roles of KRAS status remain controversial. It has become increasingly clear, however, that KRAS mutations drive primary resistance to EGFR tyrosine kinase inhibition. Until recently, mutant KRAS was not thought of as a clinically-targetable driver in lung cancers. With the expansion of our knowledge regarding the biology of KRAS-mutant lung cancers and the role of MEK and PI3K/mTOR inhibition, the face of targeted therapeutics for this genomic subset of patients is slowly beginning to change.

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KRAS-Mutant Lung Cancers in the Era of Targeted Therapy

Naidoo

Drilon

2015

Advances in Experimental Medicine and Biology

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KRAS Mutations as Prognostic and Predictive Markers in Non–Small Cell Lung Cancer

Martin

Leighl

Tsao

et al. 2013

Journal of Thoracic Oncology

114

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A greater understanding of non-small-cell lung cancer at a molecular level has led to the identification of an increasing number of driver mutations. Extensive research of the KRAS gene as well as specific mutations has established its role in tumorigenesis. Nevertheless, the role of KRAS oncogene in non-small-cell lung cancer remains unclear. Recent studies indicated that mutant KRAS could be predictive of lack of response to chemotherapy, but large pooled analysis failed to confirm this result. The predictive value of KRAS mutation and EGFR-TKI treatment is more ambiguous with some recent evidence suggesting that it may be a negative predictive biomarker. This review provides an overview of RAS biology, assesses the utility of KRAS as a prognostic marker, and evaluates its role as a predictive marker for response to chemotherapy and EGFR-TKIs. In addition, we review some current studies that are targeting the KRAS pathway.

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KRAS Mutation Status Is Associated with Enhanced Dependency on Folate Metabolism Pathways in Non–Small Cell Lung Cancer Cells

Moran

Trusk

Pry

et al. 2014

Molecular Cancer Therapeutics

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KRAS gene mutation is linked to poor prognosis and resistance to therapeutics in non-small cell lung cancer (NSCLC). In this study, we have explored the possibility of exploiting inherent differences in KRAS-mutant cell metabolism for treatment. This study identified a greater dependency on folate metabolism pathways in KRAS mutant compared with KRAS wild-type NSCLC cell lines. Microarray gene expression and biologic pathway analysis identified higher expression of folate metabolism-and purine synthesis-related pathways in KRASmutant NSCLC cells compared with wild-type counterparts. Moreover, pathway analysis and knockdown studies suggest a role for MYC transcriptional activity in the expression of these pathways in KRAS-mutant NSCLC cells. Furthermore, KRAS knockdown and overexpression studies demonstrated the ability of KRAS to regulate expression of genes that comprise folate metabolism pathways. Proliferation studies demonstrated higher responsiveness to methotrexate, pemetrexed, and other antifolates in KRAS-mutant NSCLC cells. Surprisingly, KRAS gene expression is downregulated in KRAS wild-type and KRAS-mutant cells by antifolates, which may also contribute to higher efficacy of antifolates in KRAS-mutant NSCLC cells. In vivo analysis of multiple tumorgraft models in nude mice identified a KRAS-mutant tumor among the pemetrexedresponsive tumors and also demonstrated an association between expression of the folate pathway gene, methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), and antifolate activity. Collectively, we identify altered regulation of folate metabolism in KRAS-mutant NSCLC cells that may account for higher antifolate activity in this subtype of NSCLC. Mol Cancer Ther; 13(6); 1611-24. Ó2014 AACR.

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KRAS mutations and outcomes for patients with stage IV NSCLC treated with frontline platinum/pemetrexed based chemotherapy.

Cited by 4 publications

References 0 publications

KRAS-Mutant Lung Cancers in the Era of Targeted Therapy

KRAS-Mutant Lung Cancers in the Era of Targeted Therapy

KRAS Mutations as Prognostic and Predictive Markers in Non–Small Cell Lung Cancer

KRAS Mutation Status Is Associated with Enhanced Dependency on Folate Metabolism Pathways in Non–Small Cell Lung Cancer Cells

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