Priority Research Papers:
Functional signaling pathway analysis of lung adenocarcinomas identifies novel therapeutic targets for KRAS mutant tumors
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Elisa Baldelli1,2, Guido Bellezza3, Eric B. Haura4, Lucio Crinó2, W. Douglas Cress4, Jianghong Deng1, Vienna Ludovini2, Angelo Sidoni3, Matthew B. Schabath4, Francesco Puma5, Jacopo Vannucci5, Annamaria Siggillino2, Lance A. Liotta1, Emanuel F. Petricoin III1 and Mariaelena Pierobon1
1 Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA
2 Medical Oncology Division, S. Maria della Misericordia Hospital, Perugia, Italy
3 Department of Experimental Medicine, Section of Anatomic Pathology and Histology, Medical School, University of Perugia, Perugia, Italy
4 Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
5 Department of Thoracic Surgery, University of Perugia, Perugia, Italy
Mariaelena Pierobon, email:
Keywords: signaling networks, KRAS mutation, laser capture microdissection, reverse phase protein microarray, non-small cell lung cancers
Received: August 24, 2015 Accepted: August 30, 2015 Published: September 30, 2015
Little is known about the complex signaling architecture of KRAS and the interconnected RAS-driven protein-protein interactions, especially as it occurs in human clinical specimens. This study explored the activated and interconnected signaling network of KRAS mutant lung adenocarcinomas (AD) to identify novel therapeutic targets.
Thirty-four KRAS mutant (MT) and twenty-four KRAS wild-type (WT) frozen biospecimens were obtained from surgically treated lung ADs. Samples were subjected to laser capture microdissection and reverse phase protein microarray analysis to explore the expression/activation levels of 150 signaling proteins along with co-activation concordance mapping. An independent set of 90 non-small cell lung cancers (NSCLC) was used to validate selected findings by immunohistochemistry (IHC).
Compared to KRAS WT tumors, the signaling architecture of KRAS MT ADs revealed significant interactions between KRAS downstream substrates, the AKT/mTOR pathway, and a number of Receptor Tyrosine Kinases (RTK). Approximately one-third of the KRAS MT tumors had ERK activation greater than the WT counterpart (p<0.01). Notably 18% of the KRAS MT tumors had elevated activation of the Estrogen Receptor alpha (ER-α) (p=0.02).This finding was verified in an independent population by IHC (p=0.03).
KRAS MT lung ADs appear to have a more intricate RAS linked signaling network than WT tumors with linkage to many RTKs and to the AKT-mTOR pathway. Combination therapy targeting different nodes of this network may be necessary to treat this group of patients. In addition, for patients with KRAS MT tumors and activation of the ER-α, anti-estrogen therapy may have important clinical implications.
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