Epidermal growth factor receptor inhibitors in non-small-cell lung cancer

The epidermal growth factor receptor (EGFR) is a cell membrane receptor that plays a key role in cancer development and in the progression of many human malignancies, including non-small-cell lung cancer (NSCLC). EGFR-dependent signaling is involved in cancer cell proliferation, apoptosis, angiogenesis, invasion and metastasis. Targeting the EGFR is a valuable molecular approach in cancer therapy. This receptor is overexpressed in up to 80% of NSCLC cases. Thus, several molecules inhibiting this critical biologic pathway have been synthesized and tested as a single agent or in combination with other anticancer modalities in a wide of clinical trials, including reversible and irreversible small tyrosine kinase inhibitors, such as gefitinib and erlotinib, dual vascular endothelial growth factor receptor EGFR tyrosine kinase inhibitors, such as vandetanib (ZD-6474), and monoclonal antibodies, such as cetuximab, which have shown promising activity in patients with NSCLC. This review focuses on the preclinical and clinical results available with EGFR inhibitors in the treatment of NSCLC patients.     

Epidermal growth factor receptor (EGFR)—MAPK—nuclear factor(NF)‐κB—IL8: A possible mechanism of particulate matter(PM) 2.5‐induced lung toxicity

Airway inflammation plays a central role in the pathophysiology of diverse pulmonary diseases. In this study, we investigated whether exposure to particulate matter (PM) 2.5, a PM with an aerodynamic diameter of less than 2.5 µm, enhances inflammation‐related toxicity in the human respiratory system through activation of the epidermal growth factor receptor (EGFR) signaling pathway. Through cytokine antibody array analysis of two extracts of PM_2.5 [water (W‐PM_2.5) and organic (O‐PM_2.5) soluble extracts] exposed to A549 (human alveolar epithelial cell), we identified eight cytokines changed their expression with W‐PM_2.5 and three cytokines with O‐PM_2.5. Among them, epidermal growth factor (EGF) was commonly up‐regulated by W‐PM_2.5 and O‐PM_2.5. Then, in both groups, we can identify the increase in EGF receptor protein levels. Likewise, increases in the phosphorylation of ERK1/2 MAP kinase and acetylation of nuclear factor(NF)‐κB were detected. We also detected an increase in IL‐8 that was related to inflammatory response. And using the erlotinib as an inhibitor of EGFR, we identified the erlotinib impaired the phosphorylation of EGFR, ERK1/2, acetylation of NF‐κB proteins and decreased IL‐8. Furthermore, at in vivo model, we were able to identify similar patterns. These results suggest that PM_2.5 may contribute to an abnormality in the human respiratory system through EGFR, MAP kinase, NF‐κB, and IL‐8 induced toxicity signaling. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1628–1636, 2017.     

表皮生长因子受体酪氨酸激酶抑制剂的耐药机制及其治疗策略

表皮生长因子受体酪氨酸激酶抑制剂在治疗非小细胞肺癌中取得了较好的疗效,但最终仍会出现耐药导致的肿瘤进展。目前的研究发现其中涉及的耐药机制多样,本文就近年来在非小细胞肺癌小分子酪氨酸激酶抑制剂治疗中存在的耐药机制及其治疗策略进行综述。     

23例非小细胞肺癌患者肺癌组织和血浆中EGFR外显子21的基因突变检测

目的证明可以从非小细胞肺癌患者血浆中检测到表皮生长因子受体(epidermal growth factorreceptor,EGFR)突变,且与肿瘤组织的突变情况相一致,建立一种从外周血液中快速、经济、准确检测EGFR外显子21基因突变的方法。方法同时取得23例非小细胞肺癌患者的肺癌组织和血浆,采用突变富集PCR方法检测外周血液中EGFR外显子21的基因突变,并将检测结果与肺癌组织的检测结果进行对比。结果 23例非小细胞肺癌患者的肺癌组织中共检测到8例EGFR外显子21突变,其中7例突变可以从患者的外周血液中检测到。结论可以从非小细胞肺癌患者外周血液中检测到EGFR突变,通过本方法,可以从外周血液中检测EGFR外显子21基因突变。     

Structure‐based pharmacophore models to probe anticancer activity of inhibitors of protein kinase B‐beta (PKB β)

Protein kinase B ‐ beta (PKBβ/Akt2) is a non‐receptor kinase that has attracted a great deal of attention as a promising cancer therapy drug target. In mammalian cells, hyperactivation of Akt2 exclusively facilitates the survival of solid tumors by interfering with cell cycle progression. This definite function of Akt2 in tumor survival/maintenance provides the basis for the development of its antagonists with the aim of desensitizing cell proliferation. In order to find novel and potent Akt2 inhibitors, structure ‐ based pharmacophore models have been developed and validated by the test set prediction. The final pharmacophore model was used for hits identification using public chemical databases. The hits were further prioritized using drug ‐ like filters which revealed 14 potential hit compounds having novel chemical scaffolds. Our results elucidate the importance of three hydrogen bond acceptors (A), one hydrogen bond donor (D), one hydrophobic group (H), and one positive ionic charge (P) toward inhibition of the Ak2. One of our selected hits showed 68% cell apoptosis at 8 μg/ml concentration. We proposed various chemical scaffolds including benzamide, carboxamide, and methyl benzimidazole targeting Akt2 and thus may act as potential leads for the further development of new anticancer agents.     

Noteworthy effect of slight variation in aliphatic chain length of trisubstituted imidazole inhibitors against epidermal growth factor receptor L858R/T790M/C797S mutant in cancer therapy

11h is a very potent inhibitor against epidermal growth factor receptor triple mutation L858R/T790M/C797S (EGFR^TM) with 13‐fold stronger potency than the FDA‐approved osimertinib. Recently, two new EGFR^TM inhibitors, 11d and 11e , were reported which revealed 2.8‐ and 2.3‐fold stronger potency than 11h , respectively. 11h , 11d, and 11e have the same structures but differ only in their aliphatic chain length. However, the exact effects of differential aliphatic chain length on the inhibitory potencies of these compounds require further elaboration at the atomistic level, hence the objective of this report. Various computational tools were employed for this purpose. From our findings, it was revealed that van der Waals (vdW) interactions modulate the binding mechanisms of these inhibitors and play the most important role in the differential inhibitory activities of 11d , 11h, and 11e . The strong hydrogen bond formation between the aliphatic chain of 11d and key residue ARG841 was recognized as the reason for its higher activity and inhibitory potency relative to 11h and 11e . Moreover, the extension of the N‐terminal loop into the active site for vdW interaction with the phenyl group of 11e and carbon–hydrogen bond formed between the aliphatic chain of 11e and LEU718 engendered a higher activity of 11e than 11h .     

Second-generation epidermal growth factor tyrosine kinase inhibitors in non-small cell lung cancer

Inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) has an established role in the treatment of advanced non-small cell lung cancer. The first-generation EGFR inhibitors erlotinib and gefitinib have been approved for treatment in the second- and third-line setting. Second-generation EGFR tyrosine kinase inhibitors are now in development aiming to improve efficacy and overcome primary and secondary resistance to the first-generation drugs. The two most common strategies being used to achieve these aims are irreversible binding of drug to target and kinase multi-targeting. This is an overview of the early clinical development of selected second-generation tyrosine kinase inhibitors focusing on the treatment of non-small cell lung cancer.     

Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors

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Identifying nonsmall‐cell lung tumours bearing the T790M EGFR TKI resistance mutation using PET imaging

Specific mutations significantly affect response to epidermal growth factor tyrosine kinase inhibitor (EGFR‐TKI) treatment in lung cancer patients. Identifying patients with these mutations remains a major clinical challenge. EGFR T790M mutation, which conveys resistance to in the present study, [¹⁸F]FEWZ was assessed in vitro to determine efficacy relative to the starting compound and in vivo to measure the biodistribution and specificity of binding to EGFR wild‐type, L858R and T790M bearing tumours. [¹⁸F]FEWZ is the first evidence of a radiolabeled third generation anilinopyrimidine‐derived tyrosine kinase inhibitor targeting T790M mutation bearing tumours in vivo.     

酪氨酸激酶抑制剂(吉非替尼、厄洛替尼、阿法替尼和奥希替尼)一线治疗表皮生长因子受体突变的晚期非小细胞肺癌的成本-效果分析

吉非替尼、厄洛替尼、阿法替尼和奥希替尼已被推荐为表皮生长因子受体突变的晚期非小细胞肺癌的一线治疗药物,但同时比较这四种酪氨酸激酶抑制剂在中国的经济性目前尚无研究.本研究旨在评价吉非替尼、厄洛替尼、阿法替尼和奥希替尼一线治疗表皮生长因子受体突变的晚期非小细胞肺癌的成本-效果性.通过构建马尔科夫模型,从中国医疗系统角度评价...     

PARP and other prospective targets for poisoning cancer cell metabolism

Increasing evidence indicates that cancer cells rewire their metabolism during tumorigenesis. The high intracellular levels of lactate and reactive oxygen species (ROS) generated during enhanced aerobic glycolysis and mitochondrial oxidative phosphorylation respectively led to oxidative stress. The detoxification of these accumulating metabolites and the equilibrium between reduced and oxidized nicotine adenine dinucleotide (NADH and NAD⁺) are two prominent mechanisms regulating redox status and hence energy homeostasis in tumors. Targeting both processes may thus be selectively cytotoxic for cancer cells. In this context, the impact of poly(ADP-ribose) polymerase (PARP) inhibitors, a class of anticancer agents employed for the treatment of DNA repair deficient tumors, on energy homeostasis and mitochondrial respiration regulation has potential clinical implications. Here we provide an overview of the metabolic reprogramming occurring in cancer cells and discuss the translational perspectives of targeting tumor metabolism and redox balance for antineoplastic therapy.     

Predicting the Molecular Mechanism of EGFR Domain II Dimer Binding Interface by Machine Learning to Identify Potent Small Molecule Inhibitor for Treatment of Cancer

Epidermal growth factor receptor (EGFR) is a transmembrane druggable target controlling cellular differentiation, proliferation, migration, survival and invasion. EGFR activation mainly occurs by its homo/hetro dimerization molecular phenomenon leading to tumor development and invasion. Several tyrosine kinase based inhibitors were discovered as potent anti-cancer drugs. However, mutations in its kinase domain confer resistance to most of these drugs. To overcome this drug resistance, development of small molecule inhibitors disrupting the EGFR Domain II dimer binding by machine learning methods are promising. Based on this insight, a structure-based drug repurposing strategy was adopted to repurpose the existing FDA approved drugs in blocking the EGFR Domain II mediated dimerization. We identified five best repurposed drug molecules showing good binding affinity at its key arm-cavity dimer interface residues by different machine learning methods. The molecular mechanisms of action of these repurposed drugs were computationally validated by molecular electrostatics potential mapping, point mutations at the dimer arm-cavity binding interface, molecular docking and receptor interaction studies. The present machine learning strategy thus forms the basis of identifying potent and putative small molecule drugs for the treatment of different types of cancer.