Integrated genomics-based discovery of new druggable kinases as a therapeutic target and cancer biomarker for lung cancer.

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e23144 Background: Since the number of lung cancer patients responding well to current standard therapies is still small, further development of new anti-cancer agents with minimum risk of adverse effect and highly sensitive cancer biomarkers is eagerly awaited. Methods: We have been developing new molecular therapies targeting oncoproteins with their biomarkers; i) To identify up-regulated genes in 120 lung cancers by the gene expression microarray representing 27,648 genes, ii) To verify the candidate genes for their low expression in 23 normal tissues, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering 407 non-small cell lung cancers (NSCLCs), iv) To verify whether they are essential for the growth/invasion of cancer cells by siRNA and antibody assays, and v) To measure their serum protein levels by ELISA in 343 lung cancer patients. Results: We identified 50 druggable oncoproteins and selected a LSERT (lung cancer-specific receptor tyrosine kinase). Strong LSERT protein expression was associated with poor prognosis for NSCLC patients (P < 0.0001; N = 407) as confirmed by multivariate analysis. We established an ELISA to measure serum LSERT (a cleaved form of its extracellular domain) and found that the proportion of serum LSERT-positive cases was 149 (56.4%) of 264 NSCLC and 35 (44.3%) of 79 SCLC patients, while only 6 (4.7%) of 127 healthy volunteers were falsely diagnosed. A combined ELISA for both LSERT and CEA classified 77.2% of the NSCLC patients as positive, and the use of both LSERT and ProGRP increased sensitivity in the detection of SCLCs up to 77.5%, while the false positive rate was 7 - 8%. Oncogenic LSERT activity was suppressed by treatment of lung cancer cells with anti-LSERT antibody or siRNA. Induction of LSERT increased the cellular growth and invasion by directly phosphorylating oncogenic driver kinase proteins for lung cancer and enhancing their downstream signaling of MAPK, AKT, and STAT3. Conclusions: Integrated cancer genomics might facilitate the development of diagnostic and prognostic biomarkers as well as therapeutic targets for small molecules, monoclonal antibodies, nucleic acid drugs, and cancer vaccines.