BackgroundEpidermal growth factor receptor (EGFR) mutations are present in the majority of patients with non-small cell lung cancer (NSCLC) responsive to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. These EGFR-dependent tumors eventually become TKI resistant, and the common secondary T790M mutation accounts for half the tumors with acquired resistance to gefitinib. However, the key proapoptotic proteins involved in TKI-induced cell death and other secondary mutations involved in resistance remain unclear. The objective of this study was to identify the mechanism of EGFR TKI-induced apoptosis and secondary resistant mutations that affect this process.Methods and FindingsTo study TKI-induced cell death and mechanisms of resistance, we used lung cancer cell lines (with or without EGFR mutations), Ba/F3 cells stably transfected with EGFR mutation constructs, and tumor samples from a gefitinib-resistant patient. Here we show that up-regulation of the BH3-only polypeptide BIM (also known as BCL2-like 11) correlated with gefitinib-induced apoptosis in gefitinib-sensitive EGFR-mutant lung cancer cells. The T790M mutation blocked gefitinib-induced up-regulation of BIM and apoptosis. This blockade was overcome by the irreversible TKI CL-387,785. Knockdown of BIM by small interfering RNA was able to attenuate apoptosis induced by EGFR TKIs. Furthermore, from a gefitinib-resistant patient carrying the activating L858R mutation, we identified a novel secondary resistant mutation, L747S in cis to the activating mutation, which attenuated the up-regulation of BIM and reduced apoptosis.ConclusionsOur results provide evidence that BIM is involved in TKI-induced apoptosis in sensitive EGFR-mutant cells and that both attenuation of the up-regulation of BIM and resistance to gefitinib-induced apoptosis are seen in models that contain the common EGFR T790M and the novel L747S secondary resistance mutations. These findings also suggest that induction of BIM may have a role in the treatment of TKI-resistant tumors.
Purpose-The purpose of this article is to review the recent advances in the atomic-level understanding of the Epidermal Growth Factor Receptor Tyrosine Kinase (EGFR-TK). We aim to highlight the current and future importance of these studies for the understanding and treatment of malignancies where EGFR-TK is improperly activated.Methods-The analysis was conducted on published crystal structures deposited in the Protein Data Bank (www.pdb.org) using the program O.Results-In this review we emphasize how recent EGFR kinase domain crystal structures can explain the mechanisms of activation for L858R and other EGFR-TK mutations, and compare these distinct activating mechanisms with those recently described for the wild-type EGFR. We suggest an atomic-level mechanism for the poor efficacy of lapatinib against tumors with activating EGFR kinase domain point mutations compared to the efficacy of gefitinib and erlotinib, and demonstrate how structural insights help our understanding of acquired resistance to these agents. We also highlight how these new molecular-level structural data are expected to affect the development of EGFR-TK targeted small molecule kinase inhibitors.Conclusion-There are now more crystal structures published for the EGFR-TK domain than for any other tyrosine kinase. This wealth of crystallographic information is beginning to describe the mechanisms by which proper regulation of EGFR-TK is lost in disease. These crystal structures are beginning to show how small molecules inhibit EGFR-TK activity and will aid development of EGFR-TK mutant targeted therapies.
Aptamers are short single-stranded DNA or RNA oligonucleotides that can selectively bind to small molecular ligands or protein targets with high affinity and specificity, by acquiring unique three-dimensional structures. Aptamers have the advantage of being highly specific, relatively small in size, non-immunogenic and can be easily stabilized by chemical modifications, thus allowing expansion of their diagnostic and therapeutic potential. Since the invention of aptamers in the early 1990s, great efforts have been made to make them clinically relevant for diseases like macular degeneration, cancer, thrombosis and inflammatory diseases. Furthermore, owing to the aforementioned advantages and unique adaptability of aptamers to point-of-care platforms, aptamer technology has created a stable niche in the field of in vitro diagnostics by enhancing the speed and accuracy of diagnoses. The aim of this review is to give an overview on aptamers, highlight the inherent therapeutic and diagnostic opportunities and challenges associated with them and present various aptamers that have reached therapeutic clinical trials, diagnostic markets or that have immediate translational potential for therapeutics and diagnostics applications.
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