Supramolecular host-guest nanosystems for overcoming cancer drug resistance

Cancer drug resistance has become one of the main challenges for the failure of chemotherapy,greatly limiting the selection and use of anticancer drugs and dashing the hopes of cancer patients.The emergence of supramolecular host-guest nanosystems has brought the field of supramolecular chemistry into the nanoworld,providing a potential solution to this challenge.Compared with conventional chemotherapeutic platforms,supramolecular host-guest nanosystems can reverse cancer drug resistance by increasing drug uptake,reducing drug efflux,activating drugs,and inhibiting DNA repair.Herein,we summarize the research progress of supramolecular host-guest nanosystems for overcoming cancer drug resistance and discuss the future research direction in this field.It is hoped that this review will provide more positive references for overcoming cancer drug resistance and promoting the development of supramolecular host-guest nanosystems.

New mechanisms of multidrug resistance: an introduction to the Cancer Drug Resistance special collection

Cancer Drug Resistance publishes contributions to understanding the biology and consequences of mechanisms that interfere with successful treatment of cancer. Since virtually all patients who die of metastatic cancer have multidrug-resistant tumors, improved treatment will require an understanding of the mechanisms of resistance to design therapies that circumvent these mechanisms, exploit these mechanisms, or inactivate these multidrug resistance mechanisms. One example of a resistance mechanism is the expression of ATP-binding cassette efflux pumps, but unfortunately, inhibition of these transporters has not proved to be the solution to overcome multidrug resistance in cancer. Other mechanisms that confer multidrug resistance, and the confluence of multiple different mechanisms (multifactorial multidrug resistance) have been identified, and it is the goal of this Special Collection to expand this catalog of potential multidrug resistance mechanisms, to explore novel ways to overcome resistance, and to present thoughtful reviews on the problem of multidrug resistance in cancer.

Autophagy-related mechanisms for treatment of multiple myeloma

Multiple myeloma(MM)is a type of hematological cancer that occurs when B cells become malignant.Various drugs such as proteasome inhibitors,immunomodulators,and compounds that cause DNA damage can be used in the treatment of MM.Autophagy,a type 2 cell death mechanism,plays a crucial role in determining the fate of B cells,either promoting their survival or inducing cell death.Therefore,autophagy can either facilitate the progression or hinder the treatment of MM disease.In this review,autophagy mechanisms that may be effective in MM cells were covered and evaluated within the contexts of unfolded protein response(UPR),bone marrow microenvironment(BMME),drug resistance,hypoxia,DNA repair and transcriptional regulation,and apoptosis.The genes that are effective in each mechanism and research efforts on this subject were discussed in detail.Signaling pathways targeted by new drugs to benefit from autophagy in MM disease were covered.The efficacy of drugs that regulate autophagy in MM was examined,and clinical trials on this subject were included.Consequently,among the autophagy mechanisms that are effective in MM,the most suitable ones to be used in the treatment were expressed.The importance of 3D models and microfluidic systems for the discovery of new drugs for autophagy and personalized treatment was emphasized.Ultimately,this review aims to provide a comprehensive overview of MM disease,encompassing autophagy mechanisms,drugs,clinical studies,and further studies.

Review of 5-FU resistance mechanisms in colorectal cancer:clinical significance of attenuated on-target effects

The emergence of chemoresistant disease during chemotherapy with 5-Fluorouracil-based(5-FU-based)regimens is an important factor in the mortality of metastatic CRC(mCRC).The causes of 5-FU resistance are multifactorial,and besides DNA mismatch repair deficiency(MMR-D),there are no widely accepted criteria for determining which CRC patients are not likely to be responsive to 5-FU-based therapy.Thus,there is a need to systematically understand the mechanistic basis for 5-FU treatment failure and an urgent need to develop new approaches for circumventing the major causes of 5-FU resistance.In this manuscript,we review mechanisms of 5-FU resistance with an emphasis on:(1)altered anabolic metabolism limiting the formation of the primary active metabolite Fluorodeoxyuridylate(5-Fluoro-2'-deoxyuridine-5'-O-monophosphate;FdUMP);(2)elevated expression or activity of the primary enzymatic target thymidylate synthase(TS);and(3)dysregulated programmed cell death as important causes of 5-FU resistance.Importantly,these causes of 5-FU resistance can potentially be overcome through the use of next-generation fluoropyrimidine(FP)polymers(e.g.,CF10)that display reduced dependence on anabolic metabolism and more potent TS inhibitory activity.

How acute myeloid leukemia(AML)escapes from FMS-related tyrosine kinase 3(FLT3)inhibitors?Still an overrated complication?

FMS-related tyrosine kinase 3(FLT3)mutations,present in about 25%-30%of acute myeloid leukemia(AML)patients,constitute one of the most frequently detected mutations in these patients.The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase(PI3K)and RAS pathways,producing increased cell proliferation and the inhibition of apoptosis.Two types of FLT3 mutations exist:FLT3-ITD and FLT3-TKD(point mutations in D835 and I836 or deletion of codon I836).A class of drugs,tyrosine-kinase inhibitors(TKI),targeting mutated FLT3,is already available with 1st and 2nd generation molecules,but only midostaurin and gilteritinib are currently approved.However,the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma,as the duration of clinical responses is generally limited to a few months.This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon.Has resistance been overlooked?Indeed,FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet(ELN)2022.Finally,several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented:new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy,hypomethylating drugs,or IDH1/2 inhibitors,Bcl2 inhibitors;novel anti-human FLT3 monoclonal antibodies(e.g.,FLT3/CD3 bispecific antibodies);FLT3-CAR T-cells;CDK4/6 kinase inhibitor(e.g.,palbociclib).

Resistance of breast cancer cells to paclitaxel is associated with low expressions of miRNA-186 and miRNA-7

Aim:Neo-adjuvant chemotherapy is a common approach for the complex treatment of breast cancer(BC)and paclitaxel(PTX)is frequently included in the therapeutic regimen.However,the effect of PTX-based treatment is hard to predict precisely based on routinely used markers.As microRNAs are considered a new promising class of biomarkers,the link between miRNA expression and PTX resistance of BC cells needs to be well investigated.This study aimed at the identification of miRNAs associated with responses of BC cells to PTX.Methods:Intrinsic PTX sensitivity and miRNA profiling were assayed in five BC cell lines to identify candidate miRNAs.Selected miRNA(n.15)expressions were analyzed by real-time-quantitative polymerase chain reaction(RT-qPCR)in BC tissue samples(n.31)obtained from a diagnostic biopsy.Results were analyzed in the context of the effect of two cycles of PTX and the effect of the completed scheme of neoadjuvant therapy.The study’s design facilitated the evaluation of the effect of PTX on cells and the identification of features of the microRNA expression profiles associated exclusively with sensitivity to this drug.Results:miR-186 and miR-7 expression in BC tissues was higher in patients with better outcomes of PTX-based neoadjuvant therapy.Conclusion:High expressions of miR-186 and miR-7 are associated with good response to PTX,whereas their low expressions may be associated with resistance to PTX in BC,indicating the possibility of developing innovative test systems for the prediction of the PTX response,which can be used before the start of neo-adjuvant chemotherapy for BC.

Unlocking antitumor immunity with adenosine receptorblockers

Tumors survive by creating a tumor microenvironment(TME)that suppresses antitumor immunity.The TME suppresses the immune system by limiting antigen presentation,inhibiting lymphocyte and natural killer(NK)cell activation,and facilitating T cell exhaustion.Checkpoint inhibitors like anti-PD-1 and anti-CTLA4 are immunostimulatory antibodies,and their blockade extends the survival of some but not all cancer patients.Extracellular adenosine triphosphate(ATP)is abundant in inflamed tumors,and its metabolite,adenosine(ADO),is a driver of immunosuppression mediated by adenosine A2A receptors(A2AR)and adenosine A2B receptors(A2BR)found on tumor-associated lymphoid and myeloid cells.This review will focus on adenosine as a key checkpoint inhibitor-like immunosuppressive player in the TME and how reducing adenosine production or blocking A2AR and A2BR enhances antitumor immunity.

Mitochondria in colorectal cancer stem cells-a target in drug resistance

Colorectal cancer(CRC)is the third most diagnosed cancer and the second most deadly type of cancer worldwide.In late diagnosis,CRC can resist therapy regimens in which cancer stem cells(CSCs)are intimately related.CSCs are a subpopulation of tumor cells responsible for tumor initiation and maintenance,metastasis,and resistance to conventional treatments.In this scenario,colorectal cancer stem cells(CCSCs)are considered an important key for therapeutic failure and resistance.In its turn,mitochondria is an organelle involved in many mechanisms in cancer,including chemoresistance of cytotoxic drugs due to alterations in mitochondrial metabolism,apoptosis,dynamics,and mitophagy.Therefore,it is crucial to understand the mitochondrial role in CCSCs regarding CRC drug resistance.It has been shown that enhanced anti-apoptotic protein expression,mitophagy rate,and addiction to oxidative phosphorylation are the major strategies developed by CCSCs to avoid drug insults.Thus,new mitochondria-targeted drug approaches must be explored to mitigate CRC chemoresistance via the ablation of CCSCs.

Immune checkpoint inhibitors in breast cancer: development, mechanisms of resistance and potential management strategies

The use of immune checkpoint inhibitors(iCls)has increased exponentially in the past decade,although its progress specifically for breast cancer has been modest.The first U.S.Food and Drug Administration approval for ICl in breast cancer came in 2019,eight years after the first-ever approval of an ICl.At present,current indications for ICls are relevant only to a subset of patients with triple-negative breast cancer,or those displaying high microsatellite instability or deficiency in the mismatch repair protein pathway.With an increasing understanding of the limitations of using ICls,which stem from breast cancer being innately poorly immunogenic,as well as the presence of various intrinsic and acquired resistance pathways,ongoing trials are evaluating different combination therapies to overcome these barriers.In this review,we aim to describe the development timeline of ICls and resistance mechanisms limiting their utility,and summarise the available approaches and ongoing trials relevant to overcoming each resistance mechanism.

Recent advances in natural compounds inducing non-apoptotic cell death for anticancer drug resistance

The induction of cell death is recognized as a potent strategy for cancer treatment.Apoptosis is an extensively studied form of cell death,and multiple anticancer drugs exert their therapeutic effects by inducing it.Nonetheless,apoptosis evasion is a hallmark of cancer,rendering cancer cells resistant to chemotherapy drugs.Consequently,there is a growing interest in exploring novel non-apoptotic forms of cell death,such as ferroptosis,necroptosis,pyroptosis,and paraptosis.Natural compounds with anticancer properties have garnered significant attention due to their advantages,including a reduced risk of drug resistance.Over the past two decades,numerous natural compounds have been discovered to exert anticancer and anti-resistance effects by triggering these four non-apoptotic cell death mechanisms.This review primarily focuses on these four non-apoptotic cell death mechanisms and their recent advancements in overcoming drug resistance in cancer treatment.Meanwhile,it highlights the role of natural compounds in effectively addressing cancer drug resistance through the induction of these forms of non-apoptoticcell death.

Targeting regulated cell death pathways in acutemyeloid eukemia

YangAbstractThe use of the BCL2 inhibitor venetoclax has transformed the management of patients with acute myeloid leukemia(AML)who are ineligible for intensive chemotherapy.By triggering intrinsic apoptosis,the drug is an excellent illustration of how our greater understanding of molecular cell death pathways can be translated into the clinic.Nevertheless,most venetoclax-treated patients will relapse,suggesting the need to target additional regulated cell death pathways.To highlight advances in this strategy,we review the recognized regulated cell death pathways,including apoptosis,necroptosis,ferroptosis and autophagy.Next,we detail the therapeutic opportunities to trigger regulated cell death in AML.Finally,we describe the main drug discovery challenges for regulated cell death inducers and their translation into clinical trials.A better knowledge of the molecular pathways regulating cell death represents a promising strategy to develop new drugs to cure resistant or refractory AML patients,particularly those resistant to intrinsic apoptosis.

Primary and acquired resistance to first-line therapy for clear cell renal cell carcinoma

The introduction of first-line combinations had improved the outcomes for metastatic renal cell carcinoma (mRCC) compared to sunitinib. However, some patients either have inherent resistance or develop resistance as a result of the treatment. Depending on the kind of therapy employed, many factors underlie resistance to systemic therapy. Angiogenesis and the tumor immune microenvironment (TIME), nevertheless, are inextricably linked. Although angiogenesis and the manipulation of the tumor microenvironment are linked to hypoxia, which emerges as a hallmark of renal cell carcinoma (RCC) pathogenesis, it is only one of the potential elements involved in the distinctive intra- and inter-tumor heterogeneity of RCC that is still dynamic. We may be able to more correctly predict therapy response and comprehend the mechanisms underlying primary or acquired resistance by integrating tumor genetic and immunological markers. In order to provide tools for patient selection and to generate hypotheses for the development of new strategies to overcome resistance, we reviewed the most recent research on the mechanisms of primary and acquired resistance to immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) that target the vascular endothelial growth factor receptor (VEGFR).We can choose patients’ treatments and cancer preventive strategies using an evolutionary approach thanks to the few evolutionary trajectories that characterize ccRCC.

miR-16-5p enhances sensitivity to RG7388 through targeting PPM1D expression(WIP1)in Childhood Acute Lymphoblastic Leukemia

Aim:Given the encouraging results of the p53-Mdm2 inhibitor RG7388 in clinical trials and the vital function of miR-16-5p in suppressing cell proliferation,the aim of the present study was to investigate the combined impact of RG7388 and miR-16-5p overexpression on the childhood acute lymphoblastic leukemia(chALL).Methods:miRTarBase and miRDB,along with KEGG and STRING databases,were used to predict miR-16-5p target genes and explore protein-protein interaction networks,respectively.B-and T-lymphoblastic cell lines,in addition to patient primary cells,were treated with RG7388.Ectopic overexpression of miR-16-5p in Nalm6 cell line was induced through cell electroporation and transfection of microRNA mimics was confirmed by qRT-PCR.Cell viability was evaluated using the MTT assay.Western blot analyses were performed to evaluate the effects of RG7388 and miR-16-5p upregulation on the protein levels of p53 and its downstream target genes in chALL cells.Paired sample t-test was employed for statistical analyses.Results:MTT assay showed RG7388-induced cytotoxicity in wild-type p53 Nalm6 cell line and p53 functional patient primary cells.However,CCRF-CEM and p53 non-functional leukemic cells indicated drug resistance.Western blot analyses validated the bioinformatics results,confirming the downregulation of WIP1,p53 stabilization,as well as overexpression of p21WAF1 and Mdm2 proteins in Nalm6 cells transfected with miR-16-5p.Moreover,enhanced sensitivity to RG7388 was observed in the transfected cells.Conclusion:This is the first study indicating the mechanistic importance of miR-16-5p overexpression in chALL and its inhibitory role in leukemia treatment when combined with the p53-Mdm2 antagonist,RG7388.These findings might be useful for researchers and clinicians to pave the way for better management of chALL.

Mechanisms and clinical implications in renal carcinoma resistance:narrative review of immune checkpoint inhibitors

Clear cell renal cell carcinoma(ccRCC)is the most common histological subtype of renal cell carcinoma.The prognosis for patients with ccRCC has improved over recent years with the use of combination therapies with an anti-programmed death-1(PD-1)backbone.This has enhanced the quality of life and life expectancy of patients with this disease.Unfortunately,not all patients benefit;eventually,most patients will develop resistance to therapy and progress.Recent molecular,biochemical,and immunological research has extensively researched antiangiogenic and immune-based treatment resistance mechanisms.This analysis offers an overview of the principles underpinning the resistance pathways related to immune checkpoint inhibitors(ICIs).Additionally,novel approaches to overcome resistance that may be considered for the trial context are discussed.

Mechanisms involved in cancer stem cell resistance in head and neck squamous cell carcinoma

Despite scientific advances in the Oncology field,cancer remains a leading cause of death worldwide.Molecular and cellular heterogeneity of head and neck squamous cell carcinoma(HNSCC)is a significant contributor to the unpredictability of the clinical response and failure in cancer treatment.Cancer stem cells(CSCs)are recognized as a subpopulation of tumor cells that can drive and maintain tumorigenesis and metastasis,leading to poor prognosis in different types of cancer.CSCs exhibit a high level of plasticity,quickly adapting to the tumor microenvironment changes,and are intrinsically resistant to current chemo and radiotherapies.The mechanisms of CSC-mediated therapy resistance are not fully understood.However,they include different strategies used by CSCs to overcome challenges imposed by treatment,such as activation of DNA repair system,anti-apoptotic mechanisms,acquisition of quiescent state and Epithelial-mesenchymal transition,increased drug efflux capacity,hypoxic environment,protection by the CSC niche,overexpression of stemness related genes,and immune surveillance.Complete elimination of CSCs seems to be the main target for achieving tumor control and improving overall survival for cancer patients.This review will focus on the multi-factorial mechanisms by which CSCs are resistant to radiotherapy and chemotherapy in HNSCC,supporting the use of possible strategies to overcome therapy failure.

Recent advances in access to overcome cancer drug resistance by nanocarrier drug delivery system

Cancer is currently one of the most intractable diseases causing human death.Although the prognosis of tumor patients has been improved to a certain extent through various modern treatment methods,multidrug resistance(MDR)of tumor cells is still a major problem leading to clinical treatment failure.Chemotherapy resistance refers to the resistance of tumor cells and/or tissues to a drug,usually inherent or developed during treatment.Therefore,an urgent need to research the ideal drug delivery system to overcome the shortcoming of traditional chemotherapy.The rapid development of nanotechnology has brought us new enlightenments to solve this problem.The novel nanocarrier provides a considerably effective treatment to overcome the limitations of chemotherapy or other drugs resulting from systemic side effects such as resistance,high toxicity,lack of targeting,and off-target.Herein,we introduce several tumor MDR mechanisms and discuss novel nanoparticle technology applied to surmount cancer drug resistance.Nanomaterials contain liposomes,polymer conjugates,micelles,dendrimers,carbon-based,metal nanoparticles,and nucleotides which can be used to deliver chemotherapeutic drugs,photosensitizers,and small interfering RNA(siRNA).This review aims to elucidate the advantages of nanomedicine in overcoming cancer drug resistance and discuss the latest developments.

Targeting metabolic vulnerabilities to overcome resistance to therapy in acute myeloid leukemia

Malignant hematopoietic cells gain metabolic plasticity, reorganize anabolic mechanisms to improve anabolic output and prevent oxidative damage, and bypass cell cycle checkpoints, eventually outcompeting normal hematopoietic cells. Current therapeutic strategies of acute myeloid leukemia (AML) are based on prognostic stratification that includes mutation profile as the closest surrogate to disease biology. Clinical efficacy of targeted therapies, e.g., agents targeting mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1 or 2, are mostly limited to the presence of relevant mutations. Recent studies have not only demonstrated that specific mutations in AML create metabolic vulnerabilities but also highlighted the efficacy of targeting metabolic vulnerabilities in combination with inhibitors of these mutations. Therefore, delineating the functional relationships between genetic stratification, metabolic dependencies, and response to specific inhibitors of these vulnerabilities is crucial for identifying more effective therapeutic regimens, understanding resistance mechanisms, and identifying early response markers, ultimately improving the likelihood of cure. In addition, metabolic changes occurring in the tumor microenvironment have also been reported as therapeutic targets. The metabolic profiles of leukemia stem cells (LSCs) differ, and relapsed/refractory LSCs switch to alternative metabolic pathways, fueling oxidative phosphorylation (OXPHOS), rendering them therapeutically resistant. In this review, we discuss the role of cancer metabolic pathways that contribute to the metabolic plasticity of AML and confer resistance to standard therapy;we also highlight the latest promising developments in the field in translating these important findings to the clinic and discuss the tumor microenvironment that supports metabolic plasticity and interplay with AML cells.

Unveiling T cell evasion mechanisms to immune checkpoint inhibitors in acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy that is associated with a high relapse rate and poor prognosis. Despite advances in immunotherapies in solid tumors and other hematologic malignancies, AML has been particularly difficult to treat with immunotherapies, as their efficacy is limited by the ability of leukemic cells to evade T cell recognition. In this review, we discuss the common mechanisms of T cell evasion in AML: (1) increased expression of immune checkpoint molecules;(2) downregulation of antigen presentation molecules;(3) induction of T cell exhaustion;and (4) creation of an immunosuppressive environment through the increased frequency of regulatory T cells. We also review the clinical investigation of immune checkpoint inhibitors (ICIs) in AML. We discuss the limitations of ICIs, particularly in the context of T cell evasion mechanisms in AML, and we describe emerging strategies to overcome T cell evasion, including combination therapies. Finally, we provide an outlook on the future directions of immunotherapy research in AML, highlighting the need for a more comprehensive understanding of the complex interplay between AML cells and the immune system.

Targeting BCL2 pathways in CLL: a story of resistance and ingenuity

Chronic lymphocytic leukemia(CLL)is common amongst leukemic malignancies,prompting dedicated investigation throughout the years.Over the last decade,the treatment for CLL has significantly advanced with agents targeting B-cell lymphoma 2(BCL2),Bruton's tyrosine kinase,and CD20.Single agents or combinations of these targets have proven efficacy.Unfortunately,resistance to one or multiple of the new treatment targets develops.Our review investigates various mechanisms of resistance to BCL2 inhibitors,including mutations in BCL2,alterations in the Bcl protein pathway,epigenetic modifications,genetic heterogeneity,Richter transformation,and alterations in oxidative phosphorylation.Additionally,the review will discuss potential avenues to overcome this resistance with novel agents such as bispecific antibodies,Bruton's tyrosine kinase(BTK)degraders,non-covalent BTK inhibitors,and chimeric antigen receptor T(CART).

Mechanisms of tyrosine kinase inhibitor resistance in renal cell carcinoma

Renal cell carcinoma(RCC),the most prevalent type of kidney cancer,is a significant cause of cancer morbidity and mortality worldwide.Antiangiogenic tyrosine kinase inhibitors(TKls),in combination with immune checkpoint inhibitors(ICls),are among the first-line treatment options for patients with advanced RCC.These therapies target the vascular endothelial growth factor receptor(VEGFR)tyrosine kinase pathway and other kinases crucial to cancer proliferation,survival,and metastasis.TKls have yielded substantial improvements in progression-free survival(PFS)and overall survival(OS)for patients with advanced RCC.However,nearly all patients eventually progress on these drugs as resistance develops.This review provides an overview of TKl resistance in RCC and explores different mechanisms of resistance,including upregulation of alternative proangiogenic pathways,epithelial-mesenchymal transition(EMT),decreased intracellular drug concentrations due to efflux pumps and lysosomal sequestration,alterations in the tumor microenvironment including bone marrow-derived cells(BMDCs)and tumor-associated fibroblasts(TAFs),and genetic factors such as single nucleotide polymorphisms(SNPs).A comprehensive understanding of these mechanisms opens the door to the development of innovative therapeutic approaches that can effectively overcome TKl resistance,thereby improving outcomes for patients with advanced RCC.