Abstract 1614: Kinases in lung squamous cell carcinoma and inhibitor matching using quantitative activity-based protein profiling

Introduction: Squamous cell carcinoma (SCC) of the lung is an aggressive tumor even at an early stage, leading to poor patient outcomes. Furthermore, few treatment options are currently available. In order to address these clinical needs and add to the arsenal of treatment options, we combine activi...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2014-10, Vol.74 (19_Supplement), p.1614-1614
Hauptverfasser: Fang, Bin, Wood, Elizabeth R., Li, Jiannong, Chen, Y. Ann, Brantley, Stephen G., Kinose, Fumi, Guan, Wei, Myers, Andrew R., Eschrich, Steven A., Haura, Eric B., Koomen, John M.
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Sprache:eng
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Zusammenfassung:Introduction: Squamous cell carcinoma (SCC) of the lung is an aggressive tumor even at an early stage, leading to poor patient outcomes. Furthermore, few treatment options are currently available. In order to address these clinical needs and add to the arsenal of treatment options, we combine activity-based protein profiling (ABPP) and liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM) biomarker measurements to evaluate ATP uptake by ∼200 kinases in frozen specimens acquired from 50 SCC patients. ABPP-LC-MRM also quantifies the displacement of ATP probes in these kinases by promiscuous inhibitors. The combination of kinase ATP uptake patterns and the interference between the drug and the ATP probe enables matching of therapeutics to individual patients. These surveys of kinase signaling landscapes can lead to novel options for patient treatment. Experimental Procedures: ABPP-LC-MRM for enrichment and quantification of kinase ATP uptake was optimized using SCC cell lines, and a library of assays was developed from extensive LC-MS/MS data from different tumor types. Biomarker measurements were made for frozen tumor and normal specimens from 50 patients. In a pooled tumor proteome, ABPP-LC-MRM evaluated the reduction in ATP probe binding to map a panel of drugs to their target kinases. Data Summary: The panel of ABPP-enriched proteins consists of >200 kinases (>15 tyrosine kinases). ABPP-LC-MRM analysis of SCC cell lines, including H157, H1581, H1703, H2170, H2286, H520, H596, and HCC366, indicates the ability to detect previously characterized oncogenic drivers. Because cancer cells have many drivers or significant plasticity in signaling, the ABPP-LC-MRM strategy enables readout of multiple kinases as targets for inhibition, which could support the design of rational combinations. For example, H2170 cells have high levels of ATP uptake by ErbB2 (matching its gene amplification), the Src family kinase, YES, and MEK isoforms. Therefore, combinations using MEKi, SRCi, and Lapatinib could have potential for treatment. In cell lines, viability assays were used to examine synergy of kinase inhibitors suggested by ABPP-LC-MRM. Comparison of kinase ATP uptake in tumor and normal tissues indicates potential drivers for each cancer that can be used for patient classification and matched to therapeutic strategies, including novel combinations of kinase inhibitors. Conclusions: Proteomic quantification of kinase ATP uptake enables the evaluat
ISSN:0008-5472
1538-7445
DOI:10.1158/1538-7445.AM2014-1614