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Specific growth inhibition by alteration of metabolic pathway using Chinese herbal medicine in tyrosine kinase inhibitor resistant non-small cell lung cancer

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中国药理学与毒理学杂志 2015年第S1期29卷 85-86页

作者： Xing-xingFAN MariaPikWONG Zhi-weiCAO Jian-linWU HuaZHOU Zhi-hongJIANG LiangLIU ElaineLai-hanLEUNG State Key Laboratory of Quality Research in Chinese Medicine Macao Institute For Applied Research in Medicine and Health Macao University of Science and Technology Macao China Department of Pathology Li Ka Shing Faculty of Medicine University of Hong Kong Hong Kong China School of Life Science Tongji University Shanghai China

OBJECTIVE Lung cancer is the leading cause of cancer death worldwide.Epidermal growth factor receptor(EGFR)mutation(s)is/are common in non-small cell lung cancer(NSCLC)in Asian population,resulting in lung tumor formation.L858 Rsubstitution mutation on exon 21 and in-flame deletion mutation on exon 19 are the two most common forms of EGFR mutation.Molecular targeted therapy using tyrosine kinase inhibitor(TKI)targeting EGFR shows promising initial response,however drug resistance is common.Therefore,it is needed to identify new inhibitors to tackle TKI-resistance.In this study,we aim to investigate the effect of multiple single purified compounds derived from Chinese herbal medicines(CMHs)on a panel of NSCLC cell lines with different EGFR mutational statuses and TKI sensitivity.We also examine the biological functional effect and drug action mechanism of these cell lines after drug treatment.METHODS We have reviewed the literature and selected ten single purified compounds derived from CMHs which exhibited the highest potential of cancer suppression effect in NSCLC.We have recruited three EGFR-dependent NSCLC cell lines for drug screening using cytotoxicity assay.A549 is used as EGFR wild-type control.Two TKI-resistant NSCLC cell lines were used,H1975 harbors double mutation(EGFRL858R+T790M)and H1650 harbors EGFRexon 19 deletion.H2228is a NSCLC cell line which harbours EML4-ALK fusion gene and was used as EGFR-independent cell line control.MTT assay was used to determine the drug efficacy and IC50 value.Then functional assays including cell cycle arrest analysis and apoptosis assay was used to determine the biological effect after drug treatment.RESULTS MTT assay revealed that six out of ten candidate agents showed significant cancer-inhibiting effects in H1650 and H1975cells.Three compounds exhibited IC50 value at micro-molar levels while another three compounds exhibited IC50 at as low as nano-molar levels.One compound exhibited specificity on EGFR-dependent NSCLC cell lines,which showed 10-fold more selective

关键词： non-small cell lung cancer EGFR TKI resistance,can

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Molecularly targeted therapies for advanced or metastatic non-small-cell lung carcinoma

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World Journal of Clinical Oncology 2013年第2期4卷 29-42页

作者： Soley Bayraktar Caio M Rocha-Lima Departments of Medical Oncology Mercy Cancer CenterArdmoreOK 73401United States University of Miami and Sylvester Comprehensive Cancer Center MiamiFL 33124United States

non-small-cell lung cancer(NSCLC)remains the leading cause of cancer-related death in both men and women in the United States.Platinum-based doublet chemotherapy has been a standard for patients with advanced stage disease.Improvements in overall survival and quality of life have been modest.Improved knowledge of the aberrant molecular signaling pathways found in NSCLC has led to the development of biomarkers with associated targeted therapeutics,thus changing the treatment paradigm for many NSCLC patients.In this review,we present a summary of many of the currently investigated biologic targets in NSCLC,discuss their current clinical trial status,and also discuss the potential for development of other targeted agents.

关键词： non-small cell lung cancer Molecular targeted therapy Vascular endothelial growth factor Epidermal growth factor receptor Tyrosine kinase inhibitors BRAF Anaplastic lymphoma kinase

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Stereotactic body radiation therapy for non-small cell lung cancer:A review

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World Journal of Clinical Oncology 2019年第1期10卷 14-27页

作者： Kavitha M Prezzano Sung Jun Ma Gregory M Hermann Charlotte I Rivers Jorge A Gomez-Suescun Anurag K Singh University at Buffalo the State University of New York Jacobs School of Medicine and Biomedical Sciences Department of Radiation Medicine Roswell Park Comprehensive Cancer Center

Stereotactic body radiation therapy(SBRT) is the treatment of choice for medically inoperable patients with early stage non-small cell lung cancer(NSCLC). A literature search primarily based on PubMed electronic databases was completed in July 2018. Inclusion and exclusion criteria were determined prior to the search, and only prospective clinical trials were included. Nineteen trials from 2005 to 2018 met the inclusion criteria, reporting the outcomes of 1434 patients with central and peripheral early stage NSCLC. Patient eligibility,prescription dose and delivery, and follow up duration varied widely. Threeyears overall survival ranged from 43% to 95% with loco-regional control of up to 98% at 3 years. Up to 33% of patients failed distantly after SBRT at 3 years. SBRT was generally well tolerated with 10%-30% grade 3-4 toxicities and a few treatment-related deaths. No differences in outcomes were observed between conventionally fractionated radiation therapy and SBRT, central and peripheral lung tumors, or inoperable and operable patients. SBRT remains a reasonable treatment option for medically inoperable and select operable patients with early stage NSCLC. SBRT has shown excellent local and regional control with toxicity rates equivalent to surgery. Decreasing fractionation schedules have been consistently shown to be both safe and effective. Distant failure is common, and chemotherapy may be considered for select patients. However, the survival benefit of additional interventions, such as chemotherapy, for early stage NSCLC treated with SBRT remains unclear.

关键词： Lung cancer non-small cell lung cancer Stereotactic body radiation therapy Stereotactic ablative radiotherapy Distant failure

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Tumour suppressor HLJ1: A potential diagnostic, preventive and therapeutic target in non-small cell lung cancer

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World Journal of Clinical Oncology 2014年第5期5卷 865-873页

作者： Meng-Feng Tsai Chi-Chung Wang Jeremy JW Chen Department of Molecular Biotechnology Dayeh University Graduate Institute of Basic Medicine Fu Jen Catholic University Institute of Biomedical Sciences Agricultural Biotechnology Center Rong Hsing Research Center for Translational Medicine National Chung-Hsing University

Lung cancer is the leading cause of cancer-related mortality throughout the world. non-small cell lung cancer(NSCLC) accounts for 85% of all diagnosed lung cancers. Despite considerable progress in the diagnosis and treatment of the disease, the overall 5-year survival rate of NSCLC patients remains lower than 15%. The most common causes of death in lung cancer patients are treatment failure and metastasis. Therefore, developing novel strategies that target both tumour growth and metastasis is an important and urgent mission for the next generation of anticancer therapy research. Heat shock proteins(HSPs), which are involved in the fundamental defence mechanism for maintaining cellular viability, are markedly activated during environmen-tal or pathogenic stress. HSPs facilitate rapid cell division, metastasis, and the evasion of apoptosis in cancer development. These proteins are essential players in the development of cancer and are prime therapeutic targets. In this review, we focus on the current understanding of the molecular mechanisms responsible for HLJ1's role in lung cancer carcinogenesis and progression. HLJ1, a member of the human HSP 40 family, has been characterised as a tumour suppressor. Research studies have also reported that HLJ1 shows promising dual anticancer effects, inhibiting both tumour growth and metastasis in NSCLC. The accumulated evidence suggests that HLJ1 is a potential biomarker and treatment target for NSCLC.

关键词： non-small cell lung cancer Metastasis HLJ1 Anticancer Biomarker

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Nexus of signaling and endocytosis in oncogenesis driven by non-small cell lung cancer-associated epidermal growth factor receptor mutants

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World Journal of Clinical Oncology 2014年第5期5卷 806-823页

作者： Byung Min Chung Eric Tom Neha Zutshi Timothy Alan Bielecki Vimla Band Hamid Band Department of Biochemistry and Molecular Biology Johns Hopkins School of Public Health Johns Hopkins University Baltimore MD 21205 United States Eppley Institute for Cancer and Allied Diseases University of Nebraska Medical Center Omaha NE 68198-6805 United States Department of Biochemistry and Molecular Biology University of Nebraska Medical Center Omaha NE 68198-6805 United States Department of Pathology and Microbiology University of Nebraska Medical Center Omaha NE 68198-6805 United States Department of Genetics Cell Biology and Anatomy College of Medicine University of Nebraska Medical Center Omaha NE 68198-6805 United States Department of Fred and Pamela Buffet Cancer Center University of Nebraska Medical Center Omaha NE 68198-6805 United States

Epidermal growth factor receptor(EGFR) controls a wide range of cellular processes, and aberrant EGFR signaling as a result of receptor overexpression and/or mutation occurs in many types of cancer. Tumor cells in non-small cell lung cancer(NSCLC) patients that harbor EGFR kinase domain mutations exhibit oncogene addiction to mutant EGFR, which confers high sensitivity to tyrosine kinase inhibitors(TKIs). As patients invariably develop resistance to TKIs, it is important to delineate the cell biological basis of mutant EGFR-induced cellular transformation since components of these pathways can serve as alternate therapeutic targets to preempt or overcome resistance. NSCLC-associated EGFR mutants are constitutively-active and induce ligandindependent transformation in nonmalignant cell lines. Emerging data suggest that a number of factors are critical for the mutant EGFR-dependent tumorigenicity, and bypassing the effects of TKIs on these pathways promotes drug resistance. For example, activation of downstream pathways such as Akt, Erk, STAT3 and Src is critical for mutant EGFR-mediated biological processes. It is now well-established that the potency and spatiotemporal features of cellular signaling by receptor tyrosine kinases such as EGFR, as well as the specific pathways activated, is determined by the nature of endocytic traffic pathways through which the active receptors traverse. Recent evidence indicates that NSCLCassociated mutant EGFRs exhibit altered endocytic trafficking and they exhibit reduced Cbl ubiquitin ligasemediated lysosomal downregulation. More recent work has shown that mutant EGFRs undergo ligand-independent traffic into the endocytic recycling compartment, a behavior that plays a key role in Src pathway activation and oncogenesis. These studies are beginning to delineate the close nexus between signaling and endocytic traffic of EGFR mutants as a key driver of oncogenicprocesses. Therefore, in this review, we will discuss the links between mutant EGFR signaling and endocytic properties, an

关键词： non-small cell lung cancer Epidermal growth factor receptor Signaling Endocytosis Src Cbl Ubiquitination

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Therapeutic strategy for postoperative recurrence in patients with non-small cell lung cancer

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World Journal of Clinical Oncology 2014年第5期5卷 1048-1054页

作者： Tokujiro Yano Tatsuro Okamoto Seiichi Fukuyama Yoshihiko Maehara Department of Thoracic Surgery National Hospital Organization Beppu Medical Center Department of Surgery and Science Graduate School of Medical Sciences Kyushu University

Postoperative recurrence occurs in approximately half of patients with non-small cell lung cancer(NSCLC), even after complete resection. Disease recurrence after surgical resection reduces the patient's life expectancy sharply. The prognosis after postoperative recurrence is considered to largely depend on both the mode of first recurrence(distant, locoregional or combined) and the treatment modality:(1) The majority of cases of postoperative recurrence involve distant metastasis with or without locoregional recurrence. Platinum-based systemic chemotherapy is practically accepted as the treatment for these diseases on the basis of evidence for original stage Ⅳ disease. The advent of both pemetrexed and molecular-targeted drugs has improved the survival of nonsquamous NSCLC and changed the chemotherapeutic algorithm for NSCLC;(2) Among patients with distant metastatic recurrence without locoregional recurrence at the primary tumor site, the metastasis is often limited in both organ and number. Such metastases are referred to as oligometastases. Local therapy, such as surgical resection and radiotherapy, has been suggested to be the first-line treatment of choice foroligometastatic recurrence; and(3) While locoregional recurrence is likely to cause troublesome symptoms, it is a potentially limited disease. Therefore, providing local control is important, and radiation is usually beneficial for treating local recurrence. In order to obtain better control of the disease and provide treatment with curative intent in patients with limited disease, the administration of concurrent platinum-based chemoradiotherapy is recommended according to the results of originally nonresectable stage ⅢA and ⅢB disease.

关键词： non-small cell lung cancer Postoperative recurrence Distant metastasis Oligometastases Local treatment Locoregional recurrence

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Estrogen receptors as the novel therapeutic biomarker in non-small cell lung cancer

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World Journal of Clinical Oncology 2014年第5期5卷 1020-1027页

作者： Hideki Kawai Department of Thoracic Surgery Akita Red Cross Hospital Kamikitate Akita 010-1495 Japan

Although a wide range of studies have addressed the relationship between estrogen receptor(ER) expression and prognosis in non-small cell lung cancer(NSCLC), that relationship remains controversial. This is in large part because there is no consensus on the rate of ER expression in NSCLC or on the intracellular distribution of ER expression. This suggests that establishing the relationship between ER expression and prognosis will require standardization of the antibodies used as well as the definition of a positive response. For example, it is supposed from previous studies that ERs in the cytoplasm and nucleus have different relationships to prognosis than ERs in the cytoplasm. Moreover, ER signaling in NSCLC is known to be affected by aromatase, progesterone receptor and epidermal growth factor receptor mutation. However, there has been little functional analysis these mutants and subtypes. This review will focus on what is known about the role of ERs in NSCLC and whether ER can be a useful prognostic marker or therapeutic target in NSCLC.

关键词： Estrogen receptor non-small cell lung cancer Epidermal growth factor receptor Fulvestrant Combined therapy

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Review of the current targeted therapies for non-small-cell lung cancer

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World Journal of Clinical Oncology 2014年第4期5卷 576-587页

作者： Kim-Son H Nguyen Joel W Neal Heather Wakelee Division of Oncology Department of Medicine Stanford University School of MedicineStanford CA 94305 United States Division of Oncology Department of Medicine Stanford University School of Medicine StanfordCA 94305 United States

The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer(NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor(EGFR), and crizotinib which targets anaplastic lymphoma kinase(ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790 Mtargeted agents CO-1686 and AZD9291, and the ALKtargeted agents ceritinib(LDK378), AP26113, alectinib(CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come.

关键词： Lung cancer non-small cell lung cancer Targeted therapies Epidermal growth factor receptor Epidermal growth factor receptor Anaplastic lymphoma kinase Anaplastic lymphoma kinase Acquired resistance

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Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer

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World Journal of Clinical Oncology 2014年第4期5卷 646-659页

作者： Kazuhiro Asami Shinji Atagi Department of Clinical Oncology National Hospital Organization Kinki-chuo Chest Medical Center Sakai CityOsaka 591-8555 Japan

First-generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer(NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858 R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Secondgeneration EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs.

关键词： Epidermal growth factor receptor mutation Epidermal growth factor receptor tyrosine kinase inhibitors non-small cell lung cancer Secondary resistance

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Erlotinib usage after prior treatment with gefitinib in advanced non-small cell lung cancer: A clinical perspective and review of published literature

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World Journal of Clinical Oncology 2014年第5期5卷 858-864页

作者： Navneet Singh Aditya Jindal Digambar Behera Department of Pulmonary Medicine Postgraduate Institute of Medical Education and Research

Erlotinib and gefitinib are among the most widely researched, used and available molecularly targeted therapies for treatment of advanced non-small cell lung cancer(NSCLC). They are both tyrosine kinase inhibitors(TKIs) of the epidermal growth factor receptor(EGFR). In the past decade, there have been reports on clinical benefit from use of erlotinib after gefitinib failure in NSCLC patients. A review of published literature on this focussed topic is provided herein. Pooled analysis of published literature shows that majority of patients were female(60.6%), non-smokers(64.5%), had adenocarcinoma histology(88.3%) and were of East Asian ethnicity(92.3%). Presence of sensitizing EGFR mutation was detected in 48.4% of subjects. Disease control rates with prior gefitinib therapy and with subsequent erlotinib treatment were 79.4% and 45.4% respectively. Based upon our review, the most important predictive factor for clinical benefit from erlotinib identified was previous response to gefitinib. The exact explanations for the potential benefit from erlotinib use in this patient population is still not known and further studies are required to determine the role of molecular mechanismsespecially those related to resistance to initial EGFR TKI therapy.

关键词： Gefitinib Erlotinib non-small cell lung cancer Epidermal growth factor receptor Tyrosine kinase inhibitor

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