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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 | 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 |
| 3 | 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 |
| 4 | 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 |
| 5 | 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 |
| 6 | 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 |
| 7 | 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 |
| 8 | 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 |
| 9 | 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 |
| 10 | 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 |
| 11 | 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 |
| 12 | 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 |
| 13 | MicroRNAs in neuroblastoma tumorigenesis,therapy resistance,and disease evolution显示文摘Neuroblastoma(NB)deriving from neural crest cells is the most common extra-cranial solid cancer at infancy.NB originates within the peripheral sympathetic ganglia in adrenal medulla and along the midline of the body.Clinically,NB exhibits significant heterogeneity stretching from spontaneous regression to rapid progression to therapy resistance.MicroRNAs(miRNAs,miRs)are small(19-22 nt in length)non-coding RNAs that regulate human gene expression at the post-transcriptional level and are known to regulate cellular signaling,growth,differentiation,death,stemness,and maintenance.Consequently,the function of miRs in tumorigenesis,progression and resistance is of utmost importance for the understanding of dysfunctional cellular pathways that lead to disease evolution,therapy resistance,and poor clinical outcomes.Over the last two decades,much attention has been devoted to understanding the functional roles of miRs in NB biology.This review focuses on highlighting the important implications of miRs within the context of NB disease progression,particularly miRs’influences on NB disease evolution and therapy resistance.In this review,we discuss the functions of both the“oncomiRs”and“tumor suppressor miRs”in NB progression/therapy resistance.These are the critical components to be considered during the development of novel miR-based therapeutic strategies to counter therapy resistance. | Natarajan Aravindan Karthikeyan Subramanian Dinesh Babu Somasundaram Terence S.Herman Sheeja Aravindan | 2019 | Cancer Drug Resistance2019，2，4： | 3 |
| 14 | Emerging targets in cancer drug resistance显示文摘Drug resistance is a complex phenomenon that frequently develops as a failure to chemotherapy during cancer treatment.Malignant cells increasingly generate resistance to various chemotherapeutic drugs through distinct mechanisms and pathways.Understanding the molecular mechanisms involved in drug resistance remains an important area of research for identification of precise targets and drug discovery to improve therapeutic outcomes.This review highlights the role of some recent emerging targets and pathways which play critical role in driving drug resistance. | Shashank Kumar Prem Prakash Kushwaha Sanjay Gupta | 2019 | Cancer Drug Resistance2019，2，2： | 3 |
| 15 | Targeted lapatinib anti-HER2/ErbB2 therapy resistance in breast cancer:opportunities to overcome a difficult problem显示文摘Approximately 20%of invasive breast cancers have upregulation/gene amplification of the oncogene human epidermal growth factor receptor-2(HER2/ErbB2).Of these,some also express steroid receptors(the so-called Luminal B subtype),whereas others do not(the HER2 subtype).HER2 abnormal breast cancers are associated with a worse prognosis,chemotherapy resistance,and sensitivity to selected anti-HER2 targeted therapeutics.Transcriptional data from over 3000 invasive breast cancers suggest that this approach is overly simplistic;rather,the upregulation of HER2 expression resulting from gene amplification is a driver event that causes major transcriptional changes involving numerous genes and pathways in breast cancer cells.Most notably,this includes a shift from estrogenic dependence to regulatory controls driven by other nuclear receptors,particularly the androgen receptor.We discuss members of the HER receptor tyrosine kinase family,heterodimer formation,and downstream signaling,with a focus on HER2 associated pathology in breast carcinogenesis.The development and application of anti-HER2 drugs,including selected clinical trials,are discussed.In light of the many excellent reviews in the clinical literature,our emphasis is on recently developed and successful strategies to overcome targeted therapy resistance.These include combining anti-HER2 agents with programmed cell death-1 ligand or cyclin-dependent kinase 4/6 inhibitors,targeting crosstalk between HER2 and other nuclear receptors,lipid/cholesterol synthesis to inhibit receptor tyrosine kinase activation,and metformin,a broadly inhibitory drug.We seek to facilitate a better understanding of new approaches to overcome anti-HER2 drug resistance and encourage exploration of two other therapeutic interventions that may be clinically useful for HER+invasive breast cancer patients. | Reema Wahdan-Alaswad Bolin Liu Ann D.Thor | 2020 | Cancer Drug Resistance2020，3，2： | 3 |
| 16 | The role of exosomal long non-coding RNAs in cancer drug resistance显示文摘One of the major challenges in oncology is drug resistance,which triggers relapse and shortens patients’survival.In order to promote drug desensitization,cancer cells require the establishment of an ideal tumor microenvironment that accomplishes specific conditions.To achieve this objective,cellular communication is a key factor.Classically,cells were believed to restrictively communicate by ligand-receptor binding,physical cell-to-cell interactions and synapses.Nevertheless,the crosstalk between tumor cells and stroma cells has also been recently reported to be mediated through exosomes,the smallest extracellular vesicles,which transport a plethora of functionally active molecules,such as:proteins,lipids,messenger RNA,DNA,microRNA or long non-coding RNA(lncRNAs).LncRNAs are RNA molecules greater than 200 base pairs that are deregulated in cancer and other diseases.Exosomal lncRNAs are highly stable and can be found in several body fluids,being considered potential biomarkers for tumor liquid biopsy.Exosomal lncRNAs promote angiogenesis,cell proliferation and drug resistance.The role of exosomal lncRNAs in drug resistance affects the main treatment strategies in oncology:chemotherapy,targeted therapy,hormone therapy and immunotherapy.Overall,knowing the molecular mechanisms by which exosomal lncRNA induce pharmacologic resistance could improve further drug development and identify drug resistance biomarkers. | Mireia Cruz De los Santos Mihnea P.Dragomir George A.Calin | 2019 | Cancer Drug Resistance2019，2，4： | 3 |
| 17 | An overview of resistance to Human epidermal growth factor receptor 2(Her2)targeted therapies in breast cancer显示文摘Breast cancer(BC)is the second most common cause of cancer-related deaths and the most frequently diagnosed cancer in females.Among breast cancer types,HER2-positive breast cancer occurs in nearly 20%of human breast cancers and is associated with increased aggressiveness,poor prognosis,and shortened overall survival.HER2+breast cancer is currently managed with multidisciplinary treatment strategies including surgery,radiation,chemotherapy,and targeted therapy.Drug resistance remains a continuing challenge,especially to targeted therapy utilizing monoclonal antibodies and tyrosine kinase inhibitors.This review discusses some of the recent molecular mechanisms that are involved in the development of resistance to Her2-targeted therapies including the PI3K/Akt/mTOR pathway,IGF-IR,Src,c-MET,the PP2A family,CD36,p27^(kip1),and miRNAs. | Ahmed M.Elshazly David A.Gewirtz | 2022 | Cancer Drug Resistance2022，5，2： | 3 |
| 18 | Sphingolipid metabolism and drug resistance in ovarian cancer显示文摘Despite progress in understanding molecular aberrations that contribute to the development and progression of ovarian cancer,virtually all patients succumb to drug resistant disease at relapse.Emerging data implicate bioactive sphingolipids and regulation of sphingolipid metabolism as components of response to chemotherapy or development of resistance.Increases in cytosolic ceramide induce apoptosis in response to therapy with multiple classes of chemotherapeutic agents.Aberrations in sphingolipid metabolism that accelerate the catabolism of ceramide or that prevent the production and accumulation of ceramide contribute to resistance to standard of care platinum-and taxane-based agents.The aim of this review is to highlight current literature and research investigating the influence of the sphingolipids and enzymes that comprise the sphingosine-1-phosphate pathway on the progression of ovarian cancer.The focus of the review is on the utility of sphingolipid-centric therapeutics as a mechanism to circumvent drug resistance in this tumor type. | Kelly M.Kreitzburg Robert C.A.Mvan Waardenburg Karina J.Yoon | 2018 | Cancer Drug Resistance2018，1，3： | 2 |
| 19 | Exosomal lncRNAs: the newest promising liquid biopsy显示文摘LncRNAs are defined as RNA transcripts greater than 200 nucleotides in length that have no or limited protein-coding potential.Basal expression of lncRNAs appeared important for various homeostatic processes,like gene imprinting cell differentiation and organogenesis.Moreover,it has been demonstrated that lncRNAs play an important role in tumorigenesis and metastasis.Some lncRNAs were stably detected in exosomes,which are widely found in body fluids.Several studies validated the use of exosomal lncRNAs as minimally invasive diagnostic and prognostic markers in several types of cancers.In addition,exosomal lncRNAs have been associated with drug resistance of tumor cells,suggesting a clinical application in cancer-targeted therapy.Despite the recent increase of studies on exosomal lncRNAs,their clinical significance in cancer diagnosis,prognosis and treatment needs to be fully explored.The methodologies for their detection with high purity and accuracy must be also improved in order to implement their use in clinical routine.This review aims to summarize the main recent technologies available for the isolation of exosomal lncRNAs,their status as a liquid biopsy as well as their future perspectives. | Marta Tellez-Gabriel Dominique Heymann | 2019 | Cancer Drug Resistance2019，2，4： | 2 |
| 20 | Emerging actionable targets to treat therapyresistant colorectal cancers显示文摘In the last two decades major improvements have been reached in the early diagnosis of colorectal cancer(CRC)and,besides chemotherapy,an ampler choice of therapeutic approaches is now available,including targeted and immunotherapy.Despite that,CRC remains a“big killer”mainly due to the development of resistance to therapies,especially when the disease is diagnosed after it is already metastatic.At the same time,our knowledge of the mechanisms underlying resistance has been rapidly expanding which allows the development of novel therapeutic options in order to overcome it.As far as resistance to chemotherapy is concerned,several contributors have been identified such as:intake/efflux systems upregulation;alterations in the DNA damage response,due to defect in the DNA checkpoint and repair systems;dysregulation of the expression of apoptotic/anti-apoptotic members of the BCL2 family;overexpression of oncogenic kinases;the presence of cancer stem cells;and the composition of the tumoral microenvironment and that of the gut microbiota.Interestingly,several mechanisms are also involved in the resistance to targeted and/or immunotherapy.For example,overexpression and/or hyperactivation and/or amplification of oncogenic kinases can sustain resistance to targeted therapy whereas the composition of the gut microbiota,as well as that of the tumoral niche,and defects in DNA repair systems are crucial for determining the response to immunotherapy.In this review we will make an overview of the main resistance mechanisms identified so far and of the new therapeutic approaches to overcome it. | Emanuela Grassilli Maria Grazia Cerrito | 2022 | Cancer Drug Resistance2022，5，1： | 2 |
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