This observation reinforces the hypothesis that Gefitinib may not directly inhibit the cell-cycle

For annotation we used the DAVID program suite. The most prominent category induced by EGFR kinase inhibitors is lysosome, ‘L’, the cytoplasmic membrane-bound organelle containing hydrolytic enzymes of intracellular degradation. Inhibitors of transcription and translation are induced, as are positive regulators of apoptosis; these effects neatly dovetail with their opposites in the suppressed categories. Interestingly, the cell-cycle inhibitors are induced by Gefitinib: apparently, the mechanisms of shutting down the cell-cycle differ among EGFR kinase inhibitors: while Erlotinib suppresses cellcycle proteins, Gefitinib induces cell-cycle inhibitors. This interesting observation deserves additional studies because, if confirmed, it could have important implications for cancer treatments. Steroid hormone receptor activity was conspicuous, particularly in the Gefitinib-induced set. While its significance is currently Bortezomib unknown, we note the nexus between EGFR inhibition and INCB28060 androgen activity, that anti-estrogens are used combined with Gefitinib against breast and lung cancers, whereas corticosteroids are used to treat side-effects of Gefitinib. Because EGFR activation often plays important role in cancers, many teams used various inhibitor agents, microarray platforms and experimental approaches in transcriptional studies of EGFR inhibition. We identified such studies, and then, used RankProd to combine data for metaanalysis. Several studies used multiple cell types, which were compared separately, producing 43 individual pair-wise comparisons. We used Venn diagrams to compare overlaps among genes lists. Genes regulated by individual kinase inhibitors significantly overlap with the genes tagged as regulated by all inhibitors. 306 genes are induced and 247 are suppressed by every kinase inhibitor. We separately analyzed these genes: all kinase inhibitors suppressed nuclear materiel, translational machinery, protein kinases, cell migration, ECM binding, and regulators of apoptosis; conversely, all inhibitors induced DNA binding proteins, particularly inhibitors of transcription. We analyzed separately the sets of genes responding to Gefitinib, Erlotinib, and the non-Gefitinib inhibitors. A caveat in this analysis is that differentially reaching statistical significance does not necessarily mean differential transcriptional responses. Negative regulators of transcription are suppressed by Gefitinib. This is surprising because in parallel to other kinase inhibitors, Gefitinib suppresses positive regulators of transcription. We hypothesize that Gefitinib induces very specific transcriptional responses, over a background of general inhibition of transcription. The transcription/translation machinery is, as expected, suppressed by the non-Gefitinib inhibitors, while inhibitors of protein transport, lysosomal degradation and transcription are induced. Unanticipated, Gefitinib induces the cell-cycle machinery. This is an unexpected response to EGFR inhibition and we note that Gefitinib, unlike Erlotinib and other kinase inhibitors, does not generally suppress cell-cycle genes. Confirming the above, the non-Gefitinib kinase inhibitors specifically suppressed the cell-cycle machinery.

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