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Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors

null

《医学前沿（英文）》 2016年 第10卷 第4期   页码 383-388 doi: 10.1007/s11684-016-0488-1

摘要：

The tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer (NSCLC). Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 (osimertinib; Tagrisso) is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9–13 months of therapy. The mechanisms of resistance to third-generation inhibitors reported to date include the EGFR C797S mutation, EGFR L718Q mutation, and amplifications of HER-2, MET, or ERBB2. To overcome the acquired resistance to AZD9291, EAI045 was discovered and recently reported to be an allosteric EGFR inhibitor that overcomes T790M- and C797S-mediated resistance. This review summarizes recent investigations on the mechanisms of resistance to the EGFR TKIs, as well as the latest development of EAI045 as a fourth-generation EGFR inhibitor.

关键词： EGFR     tyrosine kinase inhibitor     AZD9291     EAI045    

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Medical oncology management of advanced hepatocellular carcinoma 2019: a reality check

Amy Lee, Fa-Chyi Lee

《医学前沿（英文）》 2020年 第14卷 第3期   页码 273-283 doi: 10.1007/s11684-019-0728-2

摘要： In terms of global cancer-related deaths, hepatocellular carcinoma (HCC) has the fourth highest mortality rate. Up until 2017, treatment of advanced HCC was largely limited to sorafenib, an oral tyrosine kinase inhibitor, with little to no success in the development of alternative treatment options. However, in the past two years, there has been an unprecedented increase in both the number and type of treatment options available for HCC. As of 2019, the US FDA has approved four oral tyrosine kinase inhibitors, two immune checkpoint inhibitors, and one anti-angiogenesis antibody for the treatment of HCC. Even with this new variety, systemic treatment of advanced HCC remains largely unsatisfactory, and the median survival rate stands at approximately one year. The expected breakthrough of using immune checkpoint inhibitors in advanced HCC did not materialize in 2019. The use of immune checkpoint inhibitors in conjunction with oral tyrosine kinase inhibitors or anti-angiogenesis medications is the current clinical research trend, the results of which are eagerly anticipated. Despite limited progress in survival, HCC research is currently experiencing a period of growth and innovation, and there is hope for significant advances in the treatment of advanced HCC as the field continues to develop.

关键词： hepatocellular carcinoma     tyrosine kinase inhibitor     check point inhibitor     anti-angiogenesis    

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Targeted therapy of desmoid-type fibromatosis: mechanism, current situation, and future prospects

Zhen Wang, Jianhui Wu, Xiuyun Tian, Chunyi Hao

《医学前沿（英文）》 2019年 第13卷 第4期   页码 427-437 doi: 10.1007/s11684-018-0672-6

摘要： Desmoid-type fibromatosis (DF) is a rare monoclonal fibroblastic proliferation that is characterized by locally infiltrative but rarely metastatic lesions. Tyrosine kinase and γ-secretase inhibitors are primarily used in the targeted therapy of DF. The use of these drugs, however, is mainly based on the recommendations of retrospective studies with small sample sizes. Previous studies that focused on the mechanism, efficacy, and safety of targeted therapy for DF were reviewed to provide references for clinical applications and research. The efficacy and safety of targeted therapy were compared with those of other systemic therapy options. Targeted therapy does not provide considerable advantages in efficacy and safety over other medical treatments and is usually applied after the failure of antihormonal therapies, nonsteroidal anti-inflammatory drugs, and chemotherapy. Further studies are required to explore the mechanism, indications, and appropriate drug dosage of the targeted therapy of DF.

关键词： targeted therapy     desmoid-type fibromatosis     tyrosine kinase inhibitor     γ-secretase inhibitor    

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Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies

null

《医学前沿（英文）》 2015年 第9卷 第2期   页码 134-138 doi: 10.1007/s11684-015-0396-9

摘要：

Drug resistance is a major factor that limits the efficacy of targeted cancer therapies. In this review, we discuss the main known mechanisms of resistance to receptor tyrosine kinase inhibitors, which are the most prevalent class of targeted therapeutic agent in current clinical use. Here we focus on bypass track resistance, which involves the activation of alternate signaling molecules by tumor cells to bypass inhibition and maintain signaling output, and consider the problems of signaling pathway redundancy and how the activation of different receptor tyrosine kinases translates into intracellular signal transduction in different cancer types. This information is presented in the context of research strategies for the discovery of new targets for pharmacological intervention, with the goal of overcoming resistance in order to improve patient outcomes.

关键词： targeted therapy     drug resistance     receptor tyrosine kinases     cancer    

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Effect of inhibiting tyrosine kinase Src expression on protein phosphatase 2A and tau phosphorylation

LIU Rong, ZENG Ji, ZHOU Xinwen, WANG Jianzhi, PEI Jinjing

《医学前沿（英文）》 2008年 第2卷 第3期   页码 235-238 doi: 10.1007/s11684-008-0044-8

摘要： The aim of this study is to investigate the effect of tyrosine kinase Src on Tyrosine 307(Y307) phosphorylation, protein phosphatase 2A (PP2A) activity, and on tau phosphorylation. Specific Src siRNA was transfected into cultured mouse neuroblastoma N2a cells to inhibit the expression of Src protein, and the phosphorylation levels of PP2A Y307 and tau at different sites, as well as PP2A activity were detected at different time points after siRNA transfection. Twelve hours after siRNA transfection, the protein level of Src was dramatically decreased, with decreased PP2A Y307 phosphorylation. However, the total PP2A protein level was also decreased, together with a decreased PP2A activity. Tau was hyperphosphorylated at the Ser198/199/202 sites. Multiple factors may be involved in the cellular regulation of PP2A activity. Inhibiting Src expression could induce inactivation of PP2A and tau hyperphosphorylation.

关键词： hyperphosphorylation     PP2A activity     cellular regulation     siRNA     siRNA transfection    

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Effects of phosphatidylinositol 3-kinase inhibitor on human cervical carcinoma cells

Yuan ZHANG MD , Xiaoyan ZHANG MM , Yanhui LI MM , Xuan DU MM , Zehua WANG MD, PhD , Hongbo WANG MD ,

《医学前沿（英文）》 2009年 第3卷 第3期   页码 341-346 doi: 10.1007/s11684-009-0067-9

摘要： Phosphatidylinositol 3-kinase (PI3K) is a crucial cell survival pathway implicated in tumorigenesis because of its role in stimulating cell proliferation and suppressing apoptosis. This study was to investigate the regulation of proliferation and apoptosis by LY294002, an inhibitor of PI3K in cervical cancer cells and the expression of FLICE-like inhibitory protein (c-FLIP) . Human cervical cancer HeLa cells were used in this experiment and cultured. The cultured cells were treated with LY294002 at different concentrations (10, 25, 50 and 100µmol/L) for 6, 12, 24, and 48h before harvesting for evaluation. Cell viability was measured by 3-(4,5)-dimethylthiazol(-2-y1)-3,5-di-phenyltetrazoliumbromide (MTT) assay. Apoptosis was analyzed by flow cytometry. The expression of c-FLIP was detected by Western blot. Cell viability was inhibited by LY294002 significantly (<0.05). Flow cytometry analysis revealed that cell apoptosis was significantly increased in the presence of LY294002 as compared with the control group. Although the expression of c-FLIP was increased in a short time, the expression of c-FLIP was markedly suppressed after the treatment of LY294002 for 48h. These results suggested that the PI3K/Akt signal pathway might be involved in the regulation of cell apoptosis in cervical cancer cells. Moreover, the regulation of c-FLIP expression through PI3K/Akt signal pathway in cervical cancer cells was observed .

关键词： human cervical cancer cells     apoptosis     phosphatidylinositol 3-kinase (PI3K)/Akt     FLICE-like inhibitory protein    

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Precision medicine in acute lymphoblastic leukemia

Ching-Hon Pui

《医学前沿（英文）》 2020年 第14卷 第6期   页码 689-700 doi: 10.1007/s11684-020-0759-8

摘要： The cure rate of childhood acute lymphoblastic leukemia (ALL) has exceeded 90% in some contemporary clinical trials. However, the dose intensity of conventional chemotherapy has been pushed to its limit. Further improvement in outcome will need to rely more heavily on molecular therapeutic as well as immuno- and cellular-therapy approaches together with precise risk stratification. Children with or hyperdiploid>50 ALL who achieve negative minimal residual disease during early remission induction are suitable candidates for reduction in treatment. Patients with Philadelphia chromosome (Ph)-positive or Ph-like ALL with ABL-class fusion should be treated with dasatinib. BH3 profiling and other preclinical methods have identified several high-risk subtypes, such as hypodiplod, early T-cell precursor, immature T-cell, -rearranged, Ph-positive and -positive ALL, that may respond to BCL-2 inhibitor venetoclax. There are other fusions or mutations that may serve as putative targets, but effective targeted therapy has yet to be established. For other high-risk patients or poor early treatment responders who do not have targetable genetic lesions, current approaches that offer hope include blinatumomab, inotuzumab and CAR-T cell therapy for B-ALL, and daratumumab and nelarabine for T-ALL. With the expanding therapeutic armamentarium, we should start focus on rational combinations of targeted therapy with non-overlapping toxicities.

关键词： acute lymphoblastic leukemia     molecular therapeutics     targeted therapy     tyrosine kinase inhibitors     immunotherapy     CAR T-cell therapy    

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Four-year follow-up of patients with imatinib-resistant or intolerant chronic myeloid leukemia receiving dasatinib: efficacy and safety

Xiaojun Huang, Qian Jiang, Jianda Hu, Jianyong Li, Jie Jin, Fanyi Meng, Zhixiang Shen, Ting Liu, Depei Wu, Jianmin Wang, Jianxiang Wang

《医学前沿（英文）》 2019年 第13卷 第3期   页码 344-353 doi: 10.1007/s11684-018-0639-7

摘要： Dasatinib is a highly effective second-generation tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML). In 2007, a pivotal phase-2 study of dasatinib as second-line treatment was initiated in 140 Chinese CML patients. This report from the 4-year follow-up revealed that 73% of 59 patients in chronic phase (CML-CP) and 32% of 25 patients in accelerated phase (CML-AP) remained under treatment. The initial dosage of dasatinib for CML-CP and CML-AP patients were 100 mg once daily and 70 mg twice daily (total= 140 mg/day), respectively. The cumulative major cytogenetic response (MCyR) rate among patients with CML-CP was 66.1% (versus 50.8% at 18 months), and the median time to MCyR was 12.7 weeks. All CML-CP patients who achieved MCyR after a 4-year follow-up also achieved a complete cytogenetic response. The cumulative complete hematological response (CHR) rate among patients with CML-AP was 64% (16/25), with three CML-AP patients achieving CHR between 18 months and 4 years of follow-up; the median time to CHR was 16.4 weeks. The adverse event (AE) profile of dasatinib at 4 years was similar to that at 6 and 18 months. The most frequently reported AEs (any grade) included pleural effusion, headache, and myelosuppression. These long-term follow-up data continue to support dasatinib as a second-line treatment for Chinese patients with CML.

关键词： chronic myeloid leukemia (CML)     dasatinib     tyrosine kinase inhibitor     long-term follow-up    

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Mitogen-activated protein kinase pathway inhibitors: inhibitors for diseases?

Xu WANG MS, Xiao-Wei GONG MD, PhD, Yong JIANG MD, PhD, Yu-Hua LI PhD,

《医学前沿（英文）》 2010年 第4卷 第1期   页码 46-53 doi: 10.1007/s11684-010-0010-0

摘要： Mitogen-activated protein kinase (MAPK) signaling pathway, one of the most important signaling pathways in eukaryotic organism, is involved in multiple cellular events such as cell growth, differentiation, and apoptosis. MAPK is of great importance to the normal function of organisms, while its dysfunction results in various diseases. So far, inhibitors specifically against each subfamilies of MAP kinase have been developed, while more endeavors are needed to discover the compounds selectively targeting a particular subfamily member. Most of the kinase inhibitors exert their functions in an ATP-competitive way or a non-ATP-competitive way. Further studies on the effective mechanism of the MAPK inhibitors and their therapeutic roles in the treatment of diseases are helpful for the illumination of MAP kinase function, the development of novel inhibitors, and the therapy of diseases caused by the dysfunction of the MAPK pathway.

关键词： mitogen-activated protein kinase     drug target     inhibitor     signal transduction     disease    

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Proteomics study of Mycoplasma pneumoniae pneumonia reveals the Fc fragment of the IgG-binding protein as a serum biomarker and implicates potential therapeutic targets

《医学前沿（英文）》 2022年 第16卷 第3期   页码 378-388 doi: 10.1007/s11684-021-0840-y

摘要： Macrolide and corticosteroid resistance has been reported in patients with Mycoplasma pneumoniae (MP) pneumonia (MPP). MP clearance is difficult to achieve through antibiotic treatment in sensitive patients with severe MPP (SMPP). SMPP in children might progress to airway remodeling and even bronchiolitis/bronchitis obliterans. Therefore, identifying serum biomarkers that indicate MPP progression and exploring new targeted drugs for SMPP treatment require urgency. In this study, serum samples were collected from patients with general MPP (GMPP) and SMPP to conduct proteomics profiling. The Fc fragment of the IgG-binding protein (FCGBP) was identified as the most promising indicator of SMPP. Biological enrichment analysis indicated uncontrolled inflammation in SMPP. ELISA results proved that the FCGBP level in patients with SMPP was substantially higher than that in patients with GMPP. Furthermore, the FCGBP levels showed a decreasing trend in patients with GMPP but the opposite trend in patients with SMPP during disease progression. Connectivity map analyses identified 25 possible targeted drugs for SMPP treatment. Among them, a mechanistic target of rapamycin kinase (mTOR) inhibitor, which is a macrolide compound and a cell proliferation inhibitor, was the most promising candidate for targeting SMPP. To our knowledge, this study was the first proteomics-based characterization of patients with SMPP and GMPP.

关键词： severe Mycoplasma pneumoniae pneumonia     children     proteomics     Fc fragment of the IgG-binding protein     mechanistic target of rapamycin kinase inhibitor    

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Dual faces of SH2-containing protein-tyrosine phosphatase

null

《医学前沿（英文）》 2012年 第6卷 第3期   页码 275-279 doi: 10.1007/s11684-012-0216-4

摘要：

PTPN11, which encodes tyrosine phosphatase Shp2, is a critical gene mediating cellular responses to hormones and cytokines. Against original prediction as tumor suppressor for tyrosine phosphatases, PTPN11 was first identified as a proto-oncogene because activating mutations of this gene are associated with leukemogenesis. However, most recent experimental data suggest PTPN11/Shp2 acting as a tumor suppressor in hepatocarcinogenesis. This review focuses on the tumor-promoting or suppressing roles of the gene PTPN11/Shp2 in different cell types.

关键词： PTPN11/Shp2     leukemia     hepatocellular carcinoma     mutation    

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Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like

null

《医学前沿（英文）》 2013年 第7卷 第4期   页码 462-476 doi: 10.1007/s11684-013-0270-6

摘要：

Evaluating the effects of novel drugs on appropriate tumor models has become crucial for developing more effective therapies that target highly tumorigenic and drug-resistant cancer stem cell (CSC) populations. In this study, we demonstrate that a subset of cancer cells with CSC properties may be enriched into tumor spheroids under stem cell conditions from a non-small cell lung cancer cell line. Treating these CSC-like cells with gemcitabine alone and a combination of gemcitabine and the novel CHK1 inhibitor PF-00477736 revealed that PF-00477736 enhances the anti-proliferative effect of gemcitabine against both the parental and the CSC-like cell populations. However, the CSC-like cells exhibited resistance to gemcitabine-induced apoptosis. Collectively, the spheroid-forming CSC-like cells may serve as a model system for understanding the mechanism underlying the drug resistance of CSCs and for guiding the development of better therapies that can inhibit tumor growth and eradicate CSCs.

关键词： drug resistance     cancer stem cell     checkpoint kinase 1 (CHK1)     PF-00477736     lung cancer     tumorigenicity    

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The role of protein kinase C epsilon in neural signal transduction and neurogenic diseases

null

《医学前沿（英文）》 2011年 第5卷 第1期   页码 70-76 doi: 10.1007/s11684-011-0119-9

摘要：

Protein kinase C epsilon (PKC ?) is one of major isoforms in novel PKC family. Although it has been extensively characterized in the past decade, the role of PKC ? in neuron is still not well understood. Advances in molecular biology have now removed significant barriers to the direct investigation of PKC ? functions in vivo, and PKC ? has been increasingly implicated in the neural biological functions and associated neurogenic diseases. Recent studies have provided important insights into the influence of PKC ? on cortical processing at both the single cell level and network level. These studies provide compelling evidence that PKC ? could regulate distinct aspects of neural signal transduction and suggest that the coordinated actions of a number of molecular signals contribute to the specification and differentiation of PKC ? signal pathway in the developing brain.

关键词： protein kinase C ?     signal transduction     neurogenic disease    

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Renin--angiotensin system inhibitor is associated with the reduced risk of all-cause mortality in COVID

《医学前沿（英文）》 2022年 第16卷 第1期   页码 102-110 doi: 10.1007/s11684-021-0850-9

摘要： Consecutively hospitalized patients with confirmed coronavirus disease 2019 (COVID-19) in Wuhan, China were retrospectively enrolled from January 2020 to March 2020 to investigate the association between the use of renin–angiotensin system inhibitor (RAS-I) and the outcome of this disease. Associations between the use of RAS-I (angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)), ACEI, and ARB and in-hospital mortality were analyzed using multivariate Cox proportional hazards regression models in overall and subgroup of hypertension status. A total of 2771 patients with COVID-19 were included, with moderate and severe cases accounting for 45.0% and 36.5%, respectively. A total of 195 (7.0%) patients died. RAS-I (hazard ratio (HR)=0.499, 95% confidence interval (CI) 0.325–0.767) and ARB (HR=0.410, 95% CI 0.240–0.700) use was associated with a reduced risk of all-cause mortality among patients with COVID-19. For patients with hypertension, RAS-I and ARB applications were also associated with a reduced risk of mortality with HR of 0.352 (95% CI 0.162–0.764) and 0.279 (95% CI 0.115–0.677), respectively. RAS-I exhibited protective effects on the survival outcome of COVID-19. ARB use was associated with a reduced risk of all-cause mortality among patients with COVID-19.

关键词： COVID-19     RAS inhibitor     hypertension     all-cause mortality    

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Comparison between inhibitor and uncoupler for minimizing excess sludge production of an activated sludge

CHEN Guowei, XI Pengge, XU Deqian, YU Hanqing

《环境科学与工程前沿（英文）》 2007年 第1卷 第1期   页码 63-66 doi: 10.1007/s11783-007-0012-6

摘要： In order to study the minimization of excess sludge production, the reduction in the excess sludge production in the presence of an inhibitor and uncoupler was studied in this work. The experimental results show that such an addition could effectively reduce the production of excess sludge. With the energy uncoupling model established in this work, energy uncoupling coefficient () was used to evaluate the reduction in excess sludge production. The energy uncoupling coefficients in the presence of dinitrophenol (dNP), Zn, and Cu was 0.75, 0.46, and 0.18, respectively. The analysis demonstrated that energy spilling occurred in the presence of dNP, and that dNP was an effective uncoupler for reducing the production of excess activated sludge without affecting the microbial respiration activity.

关键词： uncoupling coefficient     Cu     minimization     presence     uncoupling    

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标题 作者 时间 类型 操作

Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors

null

期刊论文

Medical oncology management of advanced hepatocellular carcinoma 2019: a reality check

Amy Lee, Fa-Chyi Lee

期刊论文

Targeted therapy of desmoid-type fibromatosis: mechanism, current situation, and future prospects

Zhen Wang, Jianhui Wu, Xiuyun Tian, Chunyi Hao

期刊论文

Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies

null

期刊论文

Effect of inhibiting tyrosine kinase Src expression on protein phosphatase 2A and tau phosphorylation

LIU Rong, ZENG Ji, ZHOU Xinwen, WANG Jianzhi, PEI Jinjing

期刊论文

Effects of phosphatidylinositol 3-kinase inhibitor on human cervical carcinoma cells

Yuan ZHANG MD , Xiaoyan ZHANG MM , Yanhui LI MM , Xuan DU MM , Zehua WANG MD, PhD , Hongbo WANG MD ,

期刊论文

Precision medicine in acute lymphoblastic leukemia

Ching-Hon Pui

期刊论文

Four-year follow-up of patients with imatinib-resistant or intolerant chronic myeloid leukemia receiving dasatinib: efficacy and safety

Xiaojun Huang, Qian Jiang, Jianda Hu, Jianyong Li, Jie Jin, Fanyi Meng, Zhixiang Shen, Ting Liu, Depei Wu, Jianmin Wang, Jianxiang Wang

期刊论文

Mitogen-activated protein kinase pathway inhibitors: inhibitors for diseases?

Xu WANG MS, Xiao-Wei GONG MD, PhD, Yong JIANG MD, PhD, Yu-Hua LI PhD,

期刊论文

Proteomics study of Mycoplasma pneumoniae pneumonia reveals the Fc fragment of the IgG-binding protein as a serum biomarker and implicates potential therapeutic targets

期刊论文

Dual faces of SH2-containing protein-tyrosine phosphatase

null

期刊论文

Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like

null

期刊论文

The role of protein kinase C epsilon in neural signal transduction and neurogenic diseases

null

期刊论文

Renin--angiotensin system inhibitor is associated with the reduced risk of all-cause mortality in COVID

期刊论文

Comparison between inhibitor and uncoupler for minimizing excess sludge production of an activated sludge

CHEN Guowei, XI Pengge, XU Deqian, YU Hanqing

期刊论文