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| 1 | Drug resistance and combating drug resistance in cancer显示文摘Cancer is the second leading cause of death in the US.Current major treatments for cancer management include surgery,cytotoxic chemotherapy,targeted therapy,radiation therapy,endocrine therapy and immunotherapy.Despite the endeavors and achievements made in treating cancers during the past decades,resistance to classical chemotherapeutic agents and/or novel targeted drugs continues to be a major problem in cancer therapies.Drug resistance,either existing before treatment(intrinsic)or generated after therapy(acquired),is responsible for most relapses of cancer,one of the major causes of death of the disease.Heterogeneity among patients and tumors,and the versatility of cancer to circumvent therapies make drug resistance more challenging to deal with.Better understanding the mechanisms of drug resistance is required to provide guidance to future cancer treatment and achieve better outcomes.In this review,intrinsic and acquired resistance will be discussed.In addition,new discoveries in mechanisms of drug resistance will be reviewed.Particularly,we will highlight roles of ATP in drug resistance by discussing recent findings of exceptionally high levels of intratumoral extracellular ATP as well as intracellular ATP internalized from extracellular environment.The complexity of drug resistance development suggests that combinational and personalized therapies,which should take ATP into consideration,might provide better strategies and improved efficacy for fighting drug resistance in cancer. | Xuan Wang Haiyun Zhang Xiaozhuo Chen | 2019 | Cancer Drug Resistance2019，2，2： | 12 |
| 2 | Platelet activating factor/platelet activating factor receptor pathway as a potential therapeutic target in autoimmune diseases 显示文摘 | Edwards LJ Constantinescu CS | 2009 | lnflamm Allergy Drug Targets2009，8，3： | 6 |
| 3 | MEK inhibition activates STAT signaling to increase breast cancer immunogenicity via MHC-I expression显示文摘Aim:Immunotherapy and immune checkpoint inhibitors(ICI)have changed cancer care for many patients;however,breast cancers have exhibited minimal response to single agent ICI therapy.There is a significant need to identify novel targets capable of increasing cancer cell immunogenicity and response to ICIs in breast cancer.Mitogen activated protein kinase(MAPK)signaling is essential for many cellular processes but the relationship between MAPK signaling and cancer cell immunogenicity is less well understood.Recent reports suggest that MEK inhibition(MEKi)affects the tumor-immune microenvironment by altering the expression of interferon responsive PD-L1 and MHC-I through unknown mechanisms.Methods:Using western blotting and flow cytometry,we sought to determine whether MEKi affects JAK-STAT signaling upstream of PD-L1 and MHC-I expression in a panel of mouse mammary cancer and triple negative breast cancer cell lines.Results:The cell lines tested exhibited increased STAT activation in response to MEKi treatment.Furthermore,MEKi-induced MHC-I and PD-L1 expression are dependent upon STAT1 in MMTV-Neu cells.Interestingly,MEKiinduced STAT activation and interferon-responsive protein expression are abrogated with ErbB-family inhibitor co-treatment in MMTV-Neu cells,suggesting ErbB receptor signaling dependence,but not in basal-like cell lines.Importantly,analysis of basal-like breast cancer patient samples exhibited an inverse relationship between STAT1 and Ras/MAPK activation signatures.Conclusion:These findings suggest that MAPK signaling and STAT activation are inversely related in both mouse and human mammary tumors.This work also supports further study of MEKi to increase STAT signaling and potentially,immunotherapy responses through increased MHC-I and PD-L1 expression. | Derek A.Franklin Jamaal L.James Margaret L.Axelrod Justin M.Balko | 2020 | Cancer Drug Resistance2020，3，3： | 5 |
| 4 | A phase II trial of a selective c-Met inhibitor tivantinib (ARQ 197) monotherapy as a second- or third-line therapy in the patients with metastatic gastric cancer显示文摘 | Yoon-Koo Kang Kei Muro Min-Hee Ryu Hirofumi Yasui Tomohiro Nishina Baek-Yeol Ryoo Yukimasa Kamiya Shiro Akinaga Narikazu Boku | 2014 | Investigational New Drugs2014，，2： | 5 |
| 5 | Probiotics in the Management of Inflammatory Bowel Disease显示文摘 | Daisy Jonkers John Penders Ad Masclee Marieke Pierik | 2012 | Drugs2012，，6： | 5 |
| 6 | Exploiting DNA repair pathways for tumor sensitization,mitigation of resistance,and normal tissue protection in radiotherapy显示文摘More than half of cancer patients are treated with radiotherapy,which kills tumor cells by directly and indirectly inducing DNA damage,including cytotoxic DNA double-strand breaks(DSBs).Tumor cells respond to these threats by activating a complex signaling network termed the DNA damage response(DDR).The DDR arrests the cell cycle,upregulates DNA repair,and triggers apoptosis when damage is excessive.The DDR signaling and DNA repair pathways are fertile terrain for therapeutic intervention.This review highlights strategies to improve therapeutic gain by targeting DDR and DNA repair pathways to radiosensitize tumor cells,overcome intrinsic and acquired tumor radioresistance,and protect normal tissue.Many biological and environmental factors determine tumor and normal cell responses to ionizing radiation and genotoxic chemotherapeutics.These include cell type and cell cycle phase distribution;tissue/tumor microenvironment and oxygen levels;DNA damage load and quality;DNA repair capacity;and susceptibility to apoptosis or other active or passive cell death pathways.We provide an overview of radiobiological parameters associated with X-ray,proton,and carbon ion radiotherapy;DNA repair and DNA damage signaling pathways;and other factors that regulate tumor and normal cell responses to radiation.We then focus on recent studies exploiting DSB repair pathways to enhance radiotherapy therapeutic gain. | Jac A.Nickoloff Lynn Taylor Neelam Sharma Takamitsu A.Kato | 2021 | Cancer Drug Resistance2021，4，2： | 4 |
| 7 | Mechanisms of temozolomide resistance in glioblastoma-a comprehensive review显示文摘Glioblastoma(GBM)is the most common primary malignant brain tumor in adults and has an exceedingly low median overall survival of only 15 months.Current standard-of-care for GBM consists of gross total surgical resection followed by radiation with concurrent and adjuvant chemotherapy.Temozolomide(TMZ)is the first-choice chemotherapeutic agent in GBM;however,the development of resistance to TMZ often becomes the limiting factor in effective treatment.While O6-methylguanine-DNA methyltransferase repair activity and uniquely resistant populations of glioma stem cells are the most well-known contributors to TMZ resistance,many other molecular mechanisms have come to light in recent years.Key emerging mechanisms include the involvement of other DNA repair systems,aberrant signaling pathways,autophagy,epigenetic modifications,microRNAs,and extracellular vesicle production.This review aims to provide a comprehensive overview of the clinically relevant molecular mechanisms and their extensive interconnections to better inform efforts to combat TMZ resistance. | Neha Singh Alexandra Miner Lauren Hennis Sandeep Mittal | 2021 | Cancer Drug Resistance2021，4，1： | 4 |
| 8 | Linking tyrosine kinase inhibitor-mediated inflammation with normal epithelial cell homeostasis and tumor therapeutic responses显示文摘Receptor tyrosine kinases(RTKs)bearing oncogenic mutations in EGFR,ALK and ROS1 occur in a significant subset of lung adenocarcinomas.Tyrosine kinase inhibitors(TKIs)targeting tumor cells dependent on these oncogenic RTKs yield tumor shrinkage,but also a variety of adverse events.Skin toxicities,hematological deficiencies,nausea,vomiting,diarrhea,and headache are among the most common,with more acute and often fatal side effects such as liver failure and interstitial lung disease occurring less frequently.In normal epithelia,RTKs regulate tissue homeostasis.For example,EGFR maintains keratinocyte homeostasis while MET regulates processes associated with tissue remodeling.Previous studies suggest that the acneiform rash occurring in response to EGFR inhibition is a part of an inflammatory response driven by pronounced cytokine and chemokine release and recruitment of distinct immune cell populations.Mechanistically,blockade of EGFR causes a Type I interferon response within keratinocytes and in carcinoma cells driven by this RTK.This innate immune response within the tumor microenvironment(TME)involves increased antigen presentation and effector T cell recruitment that may participate in therapy response.This TKI-mediated release of inflammatory suppression represents a novel tumor cell vulnerability that may be exploited by combining TKIs with immune-oncology agents that rely on T-cell inflammation for efficacy.However,early clinical data indicate that combination therapies enhance the frequency and magnitude of the more acute adverse events,especially pneumonitis,hepatitis,and pulmonary fibrosis.Further preclinical studies to understand TKI mediated inflammation and crosstalk between normal epithelial cells,cancer cells,and the TME are necessary to improve treatment regimens for patients with RTK-driven carcinomas. | Natalia J.Gurule Lynn E.Heasley | 2018 | Cancer Drug Resistance2018，1，3： | 4 |
| 9 | Mechanisms of chemotherapy resistance in ovarian cancer显示文摘Ovarian cancer is one of the most lethal gynecologic cancers.The standard therapy for ovarian cancer has been the same for the past two decades,a combination treatment of platinum with paclitaxel.Recently,the FDA approved three new therapeutic drugs,two poly(ADP-ribose)polymerase inhibitors(olaparib and niraparib)and one vascular endothelial growth factor inhibitor(bevacizumab)as maintenance therapies for ovarian cancer.In this review,we summarize the resistance mechanisms for conventional platinum-based chemotherapy and for the newly FDA-approved drugs. | Mylena Ortiz Emma Wabel Kerry Mitchell Sachi Horibata | 2022 | Cancer Drug Resistance2022，5，2： | 4 |
| 10 | phase Ι clinical trail of Cefditoren pivoxil (M1207):pharmacokinetics in healthy volunteers显示文摘 | Li JT Hou F Lu H | 1997 | Drugs Exp Clin Res1997，23，56： | 4 |
| 11 | The use of psychotropic drugs in irritable bowel syndrome显示文摘 | Roy Dekel Douglas A Drossman Ami D Sperber | 2013 | Expert Opinion on Investigational Drugs2013，，3： | 4 |
| 12 | The importance of epithelial-mesenchymal transition and autophagy in cancer drug resistance显示文摘Epithelial-mesenchymal transition(EMT)and autophagy are both known to play important roles in the development of cancer.Subsequently,these processes are now being utilised as targets for therapy.Cancer is globally one of the leading causes of death,and,despite many advances in treatment options,patients still face many challenges.Drug resistance in cancer-therapy is a large problem,and both EMT and autophagy have been shown to contribute.However,given the context-dependent role of these processes and the complexity of the interactions between them,elucidating how they both act alone and interact is important.In this review,we provide insight into the current landscape of the interactions of autophagy and EMT in the context of malignancy,and how this ultimately may affect drug resistance in cancer therapy. | Charlotte Hill Yihua Wang | 2020 | Cancer Drug Resistance2020，3，1： | 3 |
| 13 | Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer,therapeutic treatment options for platinum-resistant ovarian cancer显示文摘The survival rates for women with ovarian cancer have shown scant improvement in recent years,with a 5-year survival rate of less than 40%for women diagnosed with advanced ovarian cancer.High-grade serous ovarian cancer(HGSOC)is the most lethal subtype where the majority of women develop recurrent disease and chemotherapy resistance,despite over 70%-80%of patients initially responding to platinum-based chemotherapy.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)signaling pathway regulates many vital processes such as cell growth,survival and metabolism.However,this pathway is frequently dysregulated in cancers including different subtypes of ovarian cancer,through amplification or somatic mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha(PIK3CA),amplification of AKT isoforms,or deletion or inactivation of PTEN.Further evidence indicates a role for the PI3K/AKT/mTOR pathway in the development of chemotherapy resistance in ovarian cancer.Thus,targeting key nodes of the PI3K/AKT/mTOR pathway is a potential therapeutic prospect.In this review,we outline dysregulation of PI3K signaling in ovarian cancer,with a particular emphasis on HGSOC and platinum-resistant disease.We review pre-clinical evidence for inhibitors of the main components of the PI3K pathway and highlight past,current and upcoming trials in ovarian cancers for different inhibitors of the pathway.Whilst no inhibitors of the PI3K/AKT/mTOR pathway have thus far advanced to the clinic for the treatment of ovarian cancer,several promising compounds which have the potential to restore platinum sensitivity and improve clinical outcomes for patients are under evaluation and in various phases of clinical trials. | Natasha Rinne Elizabeth LChristie Anastasia Ardasheva Chun Hei Kwok Nikita Demchenko Caroline Low Catherine Tralau-Stewart Christina Fotopoulou Paula Cunnea | 2021 | Cancer Drug Resistance2021，4，3： | 3 |
| 14 | Mechanisms of resistance to FGFR1 inhibitors in FGFR1-driven leukemias and lymphomas:implications for optimized treatment显示文摘Myeloid and lymphoid neoplasms with eosinophilia and FGFR1 rearrangements(MLN-eo FGFR1)disease is derived from a pluripotent hematopoietic stem cell and has a complex presentation with a myeloproliferative disorder with or without eosinophilia and frequently presents with mixed lineage T-or B-lymphomas.The myeloproliferative disease frequently progresses to AML and lymphoid neoplasms can develop into acute lymphomas.No matter the cell type involved,or clinical presentation,chromosome translocations involving the FGFR1 kinase and various partner genes,which leads to constitutive activation of downstream oncogenic signaling cascades.These patients are not responsive to treatment regimens developed for other acute leukemias and survival is poor.Recent development of specific FGFR1 inhibitors has suggested an alternative therapeutic approach but resistance is likely to evolve over time.Mouse models of this disease syndrome have been developed and are being used for preclinical evaluation of FGFR1 inhibitors.Cell lines from these models have now been developed and have been used to investigate the mechanisms of resistance that might be expected in clinical cases.So far,a V561M mutation in the kinases domain and deletion of PTEN have been recognized as leading to resistance and both operate through the PI3K/AKT signaling axis.One of the important consequences is the suppression of PUMA,a potent enforcer of apoptosis,which operates through BCL2.Targeting BCL2 in the resistant cells leads to suppression of leukemia development in mouse models,which potentially provides an opportunity to treat patients that become resistant to FGFR1 inhibitors.In addition,elucidation of molecular mechanisms underlying FGFR1-driven leukemias and lymphomas also provides new targets for combined treatment as another option to bypass the FGFR1 inhibitor resistance and improve patient outcome. | John K.Cowell Tianxiang Hu | 2021 | Cancer Drug Resistance2021，4，3： | 3 |
| 15 | Phase I study of matuzumab in combination with 5-fluorouracil, leucovorin and cisplatin (PLF) in patients with advanced gastric and esophagogastric adenocarcinomas显示文摘 | Tanja Trarbach Marta Przyborek Norbert Schleucher Steffen Heeger Christian Lüpfert Udo Vanhoefer | 2013 | Investigational New Drugs2013，，3： | 3 |
| 16 | Mitochondrial Dysfunction and Antioxidant Therapy in Sepsis显示文摘 | Milagros Rocha R. Herance S. Rovira Antonio Hernandez-Mijares Victor M. Victor | 2012 | Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders)2012，，2： | 3 |
| 17 | How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?显示文摘P-glycoprotein(ABCB1),multidrug resistance protein-1(ABCC1)and breast cancer resistance protein(ABCG2)belong to the ATP-binding cassette(ABC)superfamily of proteins that play an important physiological role in protection of the body from toxic xenobiotics and endogenous metabolites.Beyond this,these transporters determine the toxicity profile of many drugs,and confer multidrug resistance(MDR)in cancer cells associated with a poor treatment outcome of cancer patients.It has long been hypothesized that inhibition of ABC drug efflux transporters will increase drug accumulation and thereby overcome MDR,but until now no approved inhibitor of these transporters is available in the clinic.In this review we present molecular strategies to overcome this type of drug resistance and discuss for each of these strategies their promising value or indicate underlying reasons for their limited success. | Adrian C.Jaramillo Farah Al Saig Jacqueline Cloos Gerrit Jansen Godefridus J.Peters | 2018 | Cancer Drug Resistance2018，1，1： | 3 |
| 18 | Combating CHK1 resistance in triple negative breast cancer:EGFR inhibition as potential combinational therapy显示文摘Triple negative breast cancer(TNBC)is marked by a lack of expression of the Estrogen Receptor,Progesterone Receptor,and human epidermal growth factor receptor 2.Therefore,targeted therapies are being investigated based on the expression profiles of tumors.Due to the potential for acquired and intrinsic resistance,there is a need for combination therapy to overcome resistance.In the article by Lee et al.,the authors identify that,while prexasertib(a CHK1 inhibitor)lacks efficacy alone,combination with an EGFR inhibitor provides synergistic anti-tumor effects.Advances in targeted therapy for TNBC will benefit the clinical landscape for this disease,with this study initiating a new avenue of investigation. | Casey D.Stefanski Jenifer R.Prosperi | 2022 | Cancer Drug Resistance2022，5，1： | 3 |
| 19 | Liposomal targeting and drug delivery: kinetic consideration显示文摘 | Harashima H Kiwada H | 1996 | Adv Drug Deliv Rev1996，19，： | 3 |
| 20 | The roles of the human ATP-binding cassette transporters P-glycoprotein and ABCG2 in multidrug resistance in cancer and at endogenous sites: future opportunities for structure-based drug design of inhibitors显示文摘The ATP-binding cassette(ABC)transporters P-glycoprotein(P-gp)and ABCG2 are multidrug transporters that confer drug resistance to numerous anti-cancer therapeutics in cell culture.These findings initially created great excitement in the medical oncology community,as inhibitors of these transporters held the promise of overcoming clinical multidrug resistance in cancer patients.However,clinical trials of P-gp and ABCG2 inhibitors in combination with cancer chemotherapeutics have not been successful due,in part,to flawed clinical trial designs resulting from an incomplete molecular understanding of the multifactorial basis of multidrug resistance(MDR)in the cancers examined.The field was also stymied by the lack of high-resolution structural information for P-gp and ABCG2 for use in the rational structure-based drug design of inhibitors.Recent advances in structural biology have led to numerous structures of both ABCG2 and P-gp that elucidated more clearly the mechanism of transport and the polyspecific nature of their substrate and inhibitor binding sites.These data should prove useful helpful for developing even more potent and specific inhibitors of both transporters.As such,although possible pharmacokinetic interactions would need to be evaluated,these inhibitors may show greater effectiveness in overcoming ABC-dependent multidrug resistance in combination with chemotherapeutics in carefully selected subsets of cancers.Another perhaps even more compelling use of these inhibitors may be in reversibly inhibiting endogenously expressed P-gp and ABCG2,which serve a protective role at various blood-tissue barriers.Inhibition of these transporters at sanctuary sites such as the brain and gut could lead to increased penetration by chemotherapeutics used to treat brain cancers or other brain disorders and increased oral bioavailability of these agents,respectively. | Jason Goebel Jean Chmielewski Christine A.Hrycyna | 2021 | Cancer Drug Resistance2021，4，4： | 3 |
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