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Proteomes 2016, 4(2), 16; doi:10.3390/proteomes4020016

Activity-Based Proteomics Reveals Heterogeneous Kinome and ATP-Binding Proteome Responses to MEK Inhibition in KRAS Mutant Lung Cancer

1
Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
2
Proteomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
3
Cancer Informatics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
4
Department of Biostatistics & Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
5
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editors: Uwe Rix and Jacek R. Wisniewski
Received: 12 February 2016 / Revised: 30 March 2016 / Accepted: 18 April 2016 / Published: 27 April 2016
(This article belongs to the Special Issue Proteomes in Drug Development)
View Full-Text   |   Download PDF [2282 KB, uploaded 27 April 2016]   |  

Abstract

One way cancer cells can escape from targeted agents is through their ability to evade drug effects by rapidly rewiring signaling networks. Many protein classes, such as kinases and metabolic enzymes, are regulated by ATP binding and hydrolysis. We hypothesized that a system-level profiling of drug-induced alterations in ATP-binding proteomes could offer novel insights into adaptive responses. Here, we mapped global ATP-binding proteomes perturbed by two clinical MEK inhibitors, AZD6244 and MEK162, in KRAS mutant lung cancer cells as a model system harnessing a desthiobiotin-ATP probe coupled with LC-MS/MS. We observed strikingly unique ATP-binding proteome responses to MEK inhibition, which revealed heterogeneous drug-induced pathway signatures in each cell line. We also identified diverse kinome responses, indicating each cell adapts to MEK inhibition in unique ways. Despite the heterogeneity of kinome responses, decreased probe labeling of mitotic kinases and an increase of kinases linked to autophagy were identified to be common responses. Taken together, our study revealed a diversity of adaptive ATP-binding proteome and kinome responses to MEK inhibition in KRAS mutant lung cancer cells, and our study further demonstrated the utility of our approach to identify potential candidates of targetable ATP-binding enzymes involved in adaptive resistance and to develop rational drug combinations. View Full-Text
Keywords: adaptive resistance; desthiobiotin-ATP probe; KRAS mutant lung cancer; LC-MS/MS; MEK inhibitor adaptive resistance; desthiobiotin-ATP probe; KRAS mutant lung cancer; LC-MS/MS; MEK inhibitor
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Kim, J.-Y.; Stewart, P.A.; Borne, A.L.; Fang, B.; Welsh, E.A.; Chen, Y.A.; Eschrich, S.A.; Koomen, J.M.; Haura, E.B. Activity-Based Proteomics Reveals Heterogeneous Kinome and ATP-Binding Proteome Responses to MEK Inhibition in KRAS Mutant Lung Cancer. Proteomes 2016, 4, 16.

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