PURPOSE: Rearrangement of the proto-oncogene rearranged during transfection (RET) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with RET fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes. MATERIALS AND METHODS: The effects of EGF and HGF on the susceptibility of a CCDC6-RET lung cancer cell line to RET inhibitors (sunitinib, E7080, vandetanib, and sorafenib) were examined. RESULTS: CCDC6-RET lung cancer cells were highly sensitive to RET inhibitors. EGF activated epidermal growth factor receptor (EGFR) and triggered resistance to sunitinib, E7080, vandetanib, and sorafenib by transducing bypass survival signaling through ERK and AKT. Reversible EGFR-TKI (gefitinib) resensitized cancer cells to RET inhibitors, even in the presence of EGF. Endothelial cells, which are known to produce EGF, decreased the sensitivity of CCDC6-RET lung cancer cells to RET inhibitors, an effect that was inhibited by EGFR small interfering RNA (siRNA), anti-EGFR antibody (cetuximab), and EGFR-TKI (Iressa). HGF had relatively little effect on the sensitivity to RET inhibitors. CONCLUSION: EGF could trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, and endothelial cells may confer resistance to RET inhibitors by EGF. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positive lung cancer patients.
Adenocarcinoma/drug therapy/*genetics ; Cell Line, Tumor ; Cetuximab/pharmacology ; Drug Resistance, Neoplasm/drug effects/*genetics ; Epidermal Growth Factor/metabolism/*pharmacology ; *Gene Rearrangement ; Hepatocyte Growth Factor/*pharmacology ; Humans ; Indoles/pharmacology ; Lung Neoplasms/drug therapy/*genetics ; MAP Kinase Signaling System ; *Mutation ; Niacinamide/analogs & derivatives/pharmacology ; Phenylurea Compounds/pharmacology ; Piperidines/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-ret/*antagonists & inhibitors/genetics ; Pyrroles/pharmacology ; Quinazolines/pharmacology ; RNA, Small Interfering/pharmacology ; Receptor, Epidermal Growth Factor/genetics/metabolism ; Signal Transduction/drug effects ; fms-Like Tyrosine Kinase 3/metabolism

BACKGROUNDTwo recent whole-exome sequencing researches identifying somatic mutations in the ubiquitin-specific protease 8 (USP8) gene in pituitary corticotroph adenomas provide exciting advances in this field. These mutations drive increased epidermal growth factor receptor (EGFR) signaling and promote adrenocorticotropic hormone (ACTH) production. This study was to investigate whether the inhibition of USP8 activity could be a strategy for the treatment of Cushing's disease (CD).

METHODSThe anticancer effect of USP8 inhibitor was determined by testing cell viability, colony formation, apoptosis, and ACTH secretion. The immunoblotting and quantitative reverse transcription polymerase chain reaction were conducted to explore the signaling pathway by USP8 inhibition.

RESULTSInhibition of USP8-induced degradation of receptor tyrosine kinases including EGFR, EGFR-2 (ERBB2), and Met leading to a suppression of AtT20 cell growth and ACTH secretion. Moreover, treatment with USP8 inhibitor markedly induced AtT20 cells apoptosis.

CONCLUSIONSInhibition of USP8 activity could be an effective strategy for CD. It might provide a novel pharmacological approach for the treatment of CD.

Adrenocorticotropic Hormone ; metabolism ; Animals ; Apoptosis ; drug effects ; Cell Proliferation ; drug effects ; physiology ; Cell Survival ; drug effects ; physiology ; Endopeptidases ; metabolism ; Endosomal Sorting Complexes Required for Transport ; antagonists & inhibitors ; metabolism ; Enzyme Inhibitors ; pharmacology ; Humans ; Indenes ; pharmacology ; Mice ; Pyrazines ; pharmacology ; Receptor, Epidermal Growth Factor ; metabolism ; Ubiquitin Thiolesterase ; antagonists & inhibitors ; metabolism

Thirteen of 4-anilinoquinazoline derivatives with imine groups at position 6 of quinazoline ring were synthesized and their antitumor activities were evaluated by MTT assay and Western blotting analysis. Among these compounds, 13a-131 were reported first time. The MTT assay was carried out on three human cancer cell lines (A549, HepG2 and SMMC7721) with EGFR highly expressed. Among the tested compounds, 13i and 13j exhibited notable inhibition potency and their IC50 values on three cell lines were equivalent to or less than those of gefitinib. Compound 14, without imine group substituted, displayed excellent inhibitor potency only on A549 cell line. Compounds 14 and 13j were chosen to perform Western blotting analysis on A549. The results showed that both of the compounds could inhibit the expression level of phosphorylated EGFR remarkably. It was concluded that the inhibitor potency of compound 14 was almost equivalent to that of gefitinib and the inhibitor potency of 13j was better than that of gefitinib.
Aniline Compounds ; pharmacology ; Antineoplastic Agents ; pharmacology ; Cell Line, Tumor ; Humans ; Inhibitory Concentration 50 ; Phosphorylation ; Quinazolines ; pharmacology ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors

Molecular target-based cancer therapy is playing a more and more important role in cancer therapy because of its high specificity, good tolerance and so on. There are different kinds of molecular targeted drugs such as monoclonal antibodies and small molecular kinase inhibitors, and more than 50 drugs have been approved since 1997. When the first monoclonal antibody, rituximab, was on the market. The development of molecular target-based cancer therapeutics has become the main approach. Based on this, we summarized the drugs approved by FDA and introduced their mechanism of actions and clinical applications. In order to incorporate most molecular targeted drugs and describe clearly various characteristics, we divided them into four categories: drugs related to EGFR, drugs related to antiangiogenesis, drugs related to specific antigen and other targeted drugs. The purpose of this review is to provide a current status of this field and discover the main problems in the molecular targeted therapy.
Angiogenesis Inhibitors ; Antibodies, Monoclonal ; Drug Delivery Systems ; Humans ; Molecular Targeted Therapy ; Neoplasms ; drug therapy ; Protein Kinase Inhibitors ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors

BACKGROUND/AIMS: The purpose of this study was to identify predictive factors for erlotinib treatment in non-small cell lung cancer (NSCLC) patients following gefitinib failure. METHODS: Forty-five patients with NSCLC who were treated with erlotinib following gefitinib failure at Seoul National University Hospital between August 2005 and November 2011 were enrolled. Epidermal growth factor receptor (EGFR) mutation status, pathologic findings and other clinical factors, including response to tyrosine kinase inhibitors (TKIs) and progression-free survival (PFS), were evaluated. RESULTS: Of the 45 patients, 40 patients (88.8%) had adenocarcinoma. The following EGFR mutations were observed: five patients with a deletion of exon 19, six patients with an L858R mutation, three patients with wild-type EGFR, and 31 patients with unknown mutations. The response rate of erlotinib was 4.4%, and stable disease was 42.2%. The median PFS for erlotinib was 2.6 months (95% confidence interval, 1.4 to 3.7). Patients with a PFS > or = 4 months during previous gefitinib treatment had a significantly longer PFS with erlotinib (3.3 months vs. 1.6 months, respectively; p < 0.01) than patients with PFS < 4 months with gefitinib. According to multivariate analyses, PFS > or = 4 months for previous gefitinib treatment was significantly associated with prolonged PFS with erlotinib (p = 0.04). However, the response rate of gefitinib and treatment sequence were not associated with prolonged PFS with erlotinib (p = 0.28 and p = 0.67, respectively). CONCLUSIONS: Following rechallenge with the EGFR TKI erlotinib following gefitinib failure, patients who showed prolonged PFS with gefitinib benefit from erlotinib. However, further prospective studies are needed to confirm these findings.
Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/*therapeutic use ; Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/pathology ; Chi-Square Distribution ; Disease-Free Survival ; Erlotinib Hydrochloride/*therapeutic use ; Female ; Hospitals, University ; Humans ; Kaplan-Meier Estimate ; Lung Neoplasms/*drug therapy/genetics/pathology ; Male ; Middle Aged ; Multivariate Analysis ; Mutation ; Proportional Hazards Models ; Protein Kinase Inhibitors/*therapeutic use ; Quinazolines/*therapeutic use ; Receptor, Epidermal Growth Factor/antagonists & inhibitors/genetics ; Republic of Korea ; Retrospective Studies ; Risk Factors ; Salvage Therapy ; Time Factors ; Treatment Failure

OBJECTIVETo study the curative effect of Zhiyang Pingfu Liquid (ZPL) in treating epidermal growth factor receptor inhibitors (EGFRIs) associated adverse reactions of the skin.

METHODSAll 54 patients with pathologically confirmed malignant tumor had EGFRIs induced adverse reactions of the skin to various degrees. ZPL was externally applied for them all, once or twice per day, 14 days consisting of one therapeutic course. Changes of adverse skin reactions, time for symptoms relief, adverse skin reaction types suitable for ZPL were observed before and after treatment.

RESULTSEGFRIs associated skin adverse reactions were improved to various degrees after they used ZPL. The shortest symptoms relief time was 1 day while the longest was 12 days, with an average of 6.93 days and the median time 7 days. Compared with before treatment, itching, rash/scaling, acne/acneform eruptions were obviously improved (P < 0.05).

CONCLUSIONZPL could alleviate EGFRls associated adverse skin reactions, especially showed better effect on itching, rash/scaling, acne/acneform eruptions.

Antineoplastic Agents ; adverse effects ; Biomedical Research ; Drugs, Chinese Herbal ; administration & dosage ; therapeutic use ; Exanthema ; chemically induced ; Humans ; Neoplasms ; drug therapy ; Pruritus ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; Skin ; drug effects ; Skin Diseases ; drug therapy

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Standard therapeutic approaches provide modest improvement in the progression-free and overall survival, necessitating the investigation of novel therapies. We review the standard treatment options for GBM and evaluate the results obtained in clinical trials for promising novel approaches, including the inhibition of angiogenesis, targeted approaches against molecular pathways, immunotherapies, and local treatment with low voltage electric fields.
Adult ; Angiogenesis Inhibitors ; therapeutic use ; Antibodies, Monoclonal, Humanized ; therapeutic use ; Bevacizumab ; Brain Neoplasms ; therapy ; Cancer Vaccines ; therapeutic use ; Electric Stimulation Therapy ; Glioblastoma ; therapy ; Humans ; Immunotherapy ; Quinazolines ; therapeutic use ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; Snake Venoms ; therapeutic use ; Standard of Care ; Vaccines, Subunit ; therapeutic use

Both platinum-based doublet chemotherapy (PBC) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) prolong the survival of patients with advanced non-small cell lung cancer (NSCLC). In early studies, most patients underwent PBC as first-line treatment, but not all patients could afford EGFR-TKIs as second-line treatment. To understand the impact of PBC and EGFR-TKIs on NSCLC prognosis, we evaluated the association between the receipt of both regimens and overall survival (OS). Using MEDLINE and EMBASE, we identified prospective, randomized, controlled phase III clinical trials in advanced NSCLC that met the inclusion criteria: in general population with advanced NSCLC, the percentage of patients treated with both PBC and EGFR-TKIs was available in the trial and OS was reported. After collecting data from the selected trials, we correlated the percentage of patients treated with both PBC and EGFR-TKIs with the reported OS, using a weighted analysis. Fifteen phase III clinical trials--involving 11,456 adult patients in 32 arms--were included in the analysis, including 6 trials in Asian populations and 9 in non-Asian (predominantly Caucasian) populations. The OS was positively correlated with the percentage of patients treated with both PBC and EGFR-TKIs (r = 0.797, P < 0.001). The correlation was obvious in the trials in Asian populations (r = 0.936, P < 0.001) but was not statistically significant in the trials in predominantly Caucasian populations (r = 0.116, P = 0.588). These results suggest that treatment with PBC and EGFR-TKIs may provide a survival benefit to patients with advanced NSCLC, highlighting the importance of having both modalities available for therapy.
Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; pathology ; Clinical Trials, Phase III as Topic ; Disease-Free Survival ; Female ; Humans ; Lung Neoplasms ; drug therapy ; genetics ; pathology ; Male ; Middle Aged ; Neoplasm Staging ; Platinum ; administration & dosage ; Protein Kinase Inhibitors ; therapeutic use ; Randomized Controlled Trials as Topic ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; genetics ; Survival Rate

BACKGROUNDEpidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) targeted treatment has been a standard therapy for advanced non-small cell lung cancer (NSCLC), but it is not tolerated well by all patients. In China, some studies have reported that traditional Chinese medicinal herbs (TCMHs) may increase efficacy and reduce toxicity when combined with EGFR-TKI, but outside of China few studies of this kind have been attempted.

OBJECTIVEThis study is intended to systematically review the existing clinical evidence on TCMHs combined with EGFR-TKI for treatment of advanced NSCLC.

SEARCH STRATEGYPubMed, the Cochrane Library, the Excerpta Medica Database (EMBASE), the China BioMedical Literature (CBM), and the China National Knowledge Infrastructure (CNKI) and web site of the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), the World Conference of Lung Cancer (WCLC) were searched; the search included all documents published in English or Chinese before October 2013.

INCLUSION CRITERIAWe selected randomized controlled trials based on specific criteria, the most important of which was that a TCMH plus EGFR-TKI treatment group was compared with an EGFR-TKI control group in patients with advanced NSCLC.

DATA EXTRACTION AND ANALYSISThe modified Jadad scale was used to assess the quality of studies. For each included study, patient characteristics, treatment details, therapeutic approach and clinical outcomes were collected on a standardized form. When disagreements on study inclusion or data extracted from a study emerged, the consensus of all coauthors provided the resolution. The clinical outcome metrics consisted of objective response rate (ORR; complete response + partial response divided by the total number of patients), disease control rate (DCR; complete response + partial response + no change divided by the total number of patients), survival rate, improved or stabilized Karnofsky performance status (KPS), and severe toxicity. RevMan 5.0 software was used for data syntheses and analyses. Risk ratio (RR) and 95% confidence interval (CI) were calculated; if the hypothesis of homogeneity was not rejected (P>0.1, I(2)<50%), the fixed-effect model was used to calculate the summary RR and the 95% CI. Otherwise, a random-effect model was used.

RESULTSIn this review, 19 studies were included based on the selection criteria. Of them, 13 studies were of high quality and 6 studies were of low quality, according to the modified Jadad scale. When the TCMH plus EGFR-TKI treatment groups were compared with the EGFR-TKI control groups the meta-analysis demonstrated a statistically significant higher ORR (RR 1.34; 95% CI 1.15 to 1.57; P=0.000 2), DCR (RR 1.18; 95% CI 1.09 to 1.27; P<0.000 1), one-year survival rate (RR 1.21; 95% CI 1.01 to 1.44; P=0.04), 2-year survival rate (RR 1.91; 95% CI 1.26 to 2.89; P=0.002) and improved or stable KPS (RR 1.38; 95% CI 1.26 to 1.51; P<0.000 01). Severe toxicity for rash was decreased (RR 0.55; 95% CI 0.32 to 0.94; P=0.03), as were nausea and vomiting (RR 0.17; 95% CI 0.04 to 0.72; P=0.02) and diarrhea (RR 0.46; 95% CI 0.24 to 0.89; P=0.02). Sensitivity analysis indicated that findings of the meta-analysis were robust to study quality. In the funnel plot analysis, asymmetry was observed, and publication bias was indicated by Egger's test (P=0.03).

CONCLUSIONTCMH intervention can increase efficacy and reduce toxicity when combined with EGFR-TKI for advanced NSCLC, although this result requires further verification by more well designed studies.

Antineoplastic Agents ; administration & dosage ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; enzymology ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Lung Neoplasms ; drug therapy ; enzymology ; Protein Kinase Inhibitors ; administration & dosage ; Randomized Controlled Trials as Topic ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; metabolism

Small molecule covalent inhibitors, or called as irreversible inhibitors, are a type of inhibitors that exert their biological functions by irreversibly binding to target through covalent bonds. Compared with non-covalent inhibitors, covalent inhibitors have obvious advantages in bioactivity. Nevertheless, these agents may also exhibit larger toxicity once off-target effects arise. This "double-edged swords" property often leads drug researchers to avoid attaching them. In recent years, some problems such as drug resistance are difficult to be solved with reversible inhibitors leading researchers to pay more attention on the covalent inhibitors. In this review, we shall make a short summary to the recent research progress of covalent inhibitors and the interaction modes between covalent inhibitors and their target protein residues.
Amino Acids ; chemistry ; Antineoplastic Agents ; chemical synthesis ; chemistry ; therapeutic use ; Antiviral Agents ; chemical synthesis ; chemistry ; therapeutic use ; Drug Discovery ; Drug Resistance ; Enzyme Inhibitors ; chemical synthesis ; chemistry ; therapeutic use ; Hepatitis C ; drug therapy ; Humans ; Molecular Structure ; Neoplasms ; drug therapy ; Protein Binding ; Protein Kinase Inhibitors ; chemical synthesis ; chemistry ; therapeutic use ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; Serine Proteinase Inhibitors ; chemical synthesis ; chemistry ; therapeutic use