Systemic acquired resistance, NPR1, and pathogenesis-related genes in wheat and barley

In Arabidopsis, systemic acquired resistance （SAR） is established beyond the initial infection by a pathogen or is directly induced by treatment with salicylic acid （SA） or its functional analogs, 2,6-dichloroisonicotinic acid （INA） and benzothiadiazole （BTH）. NPR1 protein is considered the master regulator of SAR in both SA signal sensing and transduction. In wheat （Triticum aesfivum） and barley （Hordeum vulgare）, both pathogen infection and BTH treatment can induce broad-spectrum resistance to various diseases, including powdery mildew, leaf rust, Fusarium head blight, etc. However, three different types of SAR-like responses including acquired resistance （AR）, systemic immunity （SI）, and BTH-induced resistance （BIR） seem to be achieved by activating different gene pathways. Recent research on wheat and barley NPR1 homologs in AR and SI has provided the initial clue for understanding the mechanism of SAR in these two plant species. In this review, the specific features ofAR, Si, and BIR in wheat and barley were summarized and compared with that of SAR in model plants of Arabidopsis and rice. Research updates on downstream genes of SAR, including pathogenesis-related （PR） and BTH-induced genes, were highlighted.

Advances in the management of acquired resistance to EGFR-TKI in non-small cell lung cancer

Drugs that specifically target the tyrosine kinase domain of epidermal growth factor receptor(EGFR), such as erlotinib or gefitinib, have exhibited striking efficacy in non-small cell lung cancer(NSCLC) patients harboring activating EGFR mutations. However, acquired resistance inevitably develops and remains a serious barrier for the successful management of patients with this disease. Multiple mechanisms are reportedly involved in the process of acquired resistance, which provide new insights into the management of EGFRtyrosine kinase inhibitor(EGFR-TKI) resistance. Here, we provide an overview of the emerging treatment approaches for patients with EGFR-TKI resistance.

Systemic Acquired Resistance and Signal Transduction in Plant

Systemic acquired resistance (SAR), known as the broad-spectrum, inducible plant immunity, is a defense response triggered by pathogen infection. The response starts from the recognition of plant resistance (R) with the corresponding avirulence (avr) gene from the pathogen. There are some genes for convergence of signals downstream of different R/avr interacting partners into a single signaling pathway. Salicylic acid (SA) is required for the induction of SAR and involved in transducing the signal in target tissues. The SA signal is transduced through NPR1, a nuclear-localized protein that interacts with transcription factors that are involved in regulating SA-mediated gene expression. Some chemicals that mimic natural signaling compounds can also activate SAR. The application of biochemical activators to agriculture for plant protection is a novel idea for developing green chemical pesticide.

Effects of PI3K Inhibitor NVP-BKM120 on Acquired Resistance to Gefitinib of Human Lung Adenocarcinoma H1975 Cells

The effects of class I PI3K inhibitor NVP-BKM120 on cell proliferation, cell cycle distri- bution, cellular apoptosis, phosphorylation of several proteins of the PI3K/AKT signaling pathway and the mRNA expression levels of HIFl-ct, VEGF and MMP9 in the acquired gefitinib resistant cell line H1975 were investigated, and whether NVP-BKM120 can overcome the acquired resistance caused by the EGFR T790M mutation and the underlying mechanism were explored. MTT assay was performed to detect the effect of gefitinib, NVP-BKM120, NVP-BKM120 plus 1 ~unol/L gefitinib on growth of H1975 cells. The distribution of cell cycle and apoptosis rate of H1975 cells were examined by using flow cytometry. The mRNA expression levels of tumor-related genes such as HIFI-a, VEGF and MMP9 were detected by using real-time quantitative PCR. Western blotting was used to detect the ex- pression level of phosphorylated proteins in the PI3K/AKT signaling pathway, such as Ser473-p-AKT, Ser235/236-p-S6 and Thr70-p-4E-BP1, as well as total AKT, $6 and 4E-BP1. The results showed that the NVP-BKM120 could inhibit the growth of H1975 cells in a concentration-dependent manner, and H1975 cells were more sensitive to NVP-BKM120 than gefitinib （IC50：1.385 vs. 15.09 ~mol/L respec- tively）, whereas combination of NVP-BKM120 and gefitinib （1 ~trnol/L） did not show more obvious ef- fect than NVP-BKM120 used alone on inhibition of cell growth （P〉0.05）. NVP-BKM120 （1 ~unol/L） increased the proportion ofH1975 cells in G0~G1 phase and the effect was concentration-dependent, and 2 ~maol/L NVP-BKM120 promoted apoptosis ofH1975 cells. There was no significant difference in the proportion of H1975 cells in G0-G1 phase and apoptosis rate between NVP-BKM120-treated alone group and NVP-BKM120 plus genfitinib （1 ~unol/L）-treated group or between DMSO-treated control group and gefitinib （1 Ixmol/L）-treated alone group （P〉0.05 for all）. It was also found that the mRNA expression levels of these genes were down-regulated by NVP-BKM120 （1 ~unol/L）, and NVP-BKM120 （1 ~tmol/L） or NVP-BKM120 （1 pmol/L） plus gefitinib （1 ~tmol/L） obviously inhibited the activation of Akt, $6 and 4E-BP1 as compared with control group, but single use of gefitinib （1 pmol/L） exerted no significant effect. These data suggested that NVP-BKM120 can overcome gefitinib resistance in H1975 cells, and the combination of NVP-BKM120 and gefitinib did not have additive or synergistic effects. It was also concluded that NVP-BKM120 could overcome the acquired resistance to gefitinib by down-regulating the phosphorylated protein in PI3K/AKT signal pathways in H1975 cells, but it could not enhance the sensitivity of H 1975 cells to gefitinib.

Taking early preventive interventions to manage the challenging issue of acquired resistance to third-generation EGFR inhibitors

Although the clinical efficacies of third-generation epidermal growth factor receptor(EGFR)-tyrosine kinase in-hibitors(TKIs)such as osimertinib in the treatment of non-small cell lung cancer(NSCLC)with EGFR-activating mutations are promising,drug-acquired resistance inevitably occurs whether they are used as first-line or second-line treatment.Therefore,managing the acquired resistance to third-generation EGFR-TKIs is crucial in the clinic for improving patient survival.Great efforts have been made to develop potentially effective strategies or regimens for the treatment of EGFR-mutant NSCLC patients after relapse following these TKIs therapies with the hope that patients will continue to benefit from treatment through overcoming acquired resistance.Although this approach,which aims to overcome drug-acquired resistance,is necessary and important,it is a passive practice.Taking pre-ventive action early before disease progression to manage the unavoidable development of acquired resistance offers an equally important and efficient approach.We strongly believe that early preventive interventions using effective and tolerable combination regimens that interfere with the process of developing acquired resistance may substantially improve the outcomes of EGFR-mutant NSCLC treatment with third-generation EGFR-TKIs.Thus,this review focuses on discussing the scientific rationale and mechanism-driven strategies for delaying and even preventing the emergence of acquired resistance to third-generation EGFR-TKIs,particularly osimertinib.

Suberoylanilide hydroxamic acid overcomes erlotinib-acquired resistance via phosphatase and tensin homolog deleted on chromosome 10-mediated apoptosis in non-small cell lung cancer

Background::Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),such as erlotinib and gefitinib,are widely used to treat non-small cell lung cancer(NSCLC).However,acquired resistance is unavoidable,impairing the anti-tumor effects of EGFR-TKIs.It is reported that histone deacetylase(HDAC)inhibitors could enhance the anti-tumor effects of other antineoplastic agents and radiotherapy.However,whether the HDAC inhibitor suberoylanilide hydroxamic acid(SAHA)can overcome erlotinib-acquired resistance is not fully clear.Methods::An erlotinib-resistant PC-9/ER cell line was established through cell maintenance in a series of erlotinib-containing cultures.NSCLC cells were co-cultured with SAHA,erlotinib,or their combination,and then the viability of cells was measured by the 3-(4,5-Dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and apoptosis was determined by flow cytometry and western blotting.Finally,the expression of phosphatase and tensin homolog deleted on chromosome 10(PTEN)was assessed by western blotting.Results::The half-maximal inhibitory concentration of parental PC-9 cells was significantly lower than the established erlotinib-acquired resistant PC-9/ER cell line.PC-9/ER cells demonstrated reduced expression of PTEN compared with PC-9 and H1975 cells,and the combination of SAHA and erlotinib significantly inhibited cell growth and increased apoptosis in both PC-9/ER and H1975 cells.Furthermore,treating PC-9/ER cells with SAHA or SAHA combined with erlotinib significantly upregulated the expression of PTEN mRNA and protein compared with erlotinib treatment alone.Conclusions::PTEN deletion is closely related to acquired resistance to EGFR-TKIs,and treatment with the combination of SAHA and erlotinib showed a greater inhibitory effect on NSCLC cells than single-drug therapy.SAHA enhances the suppressive effects of erlotinib in lung cancer cells,increasing cellular apoptosis and PTEN expression.SAHA can be a potential adjuvant to erlotinib treatment,and thus,can improve the efficacy of NSCLC therapy.

Glycosylation of N-hydroxy-pipecolic acid equilibrates between systemic acquired resistance response and plant growth

N-hydroxy-pipecolic acid(NHP)activates plant systemic acquired resistance(SAR).Enhanced defense responses are typically accompanied by deficiency in plant development and reproduction.Despite of extensive studies on SAR induction,the effects of NHPmetabolismon plant growth remain largely unclear.In this study,we discovered that NHP glycosylation is a critical factor that fine-tunes the tradeoff between SAR defense and plant growth.We demonstrated that a UDP-glycosyltransferase(UGT76B1)forming NHP glycoside(NHPG)controls the NHP to NHPG ratio.Consistently,the ugt76b1 mutant exhibits enhanced SAR response and an inhibitory effect on plant growth,while UGT76B1 overexpression attenuates SAR response,promotes growth,and delays senescence,indicating that NHP levels are dependent on UGT76B1 function in the course of SAR.Furthermore,our results suggested that,upon pathogen attack,UGT76B1-mediated NHP glycosylation forms a‘‘hand brake’’on NHP accumulation by attenuating the positive regulation of NHP biosynthetic pathway genes,highlighting the complexity of SAR-associated networks.In addition,we showed that UGT76B1-mediated NHP glycosylation in the local site is important for fine-tuning SAR response.Our results implicate that engineering plant immunity through manipulating the NHP/NHPG ratio is a promising method to balance growth and defense response in crops.

Regulatory and Functional Aspects of Indolic Metabolism in Plant Systemic Acquired Resistance

Tryptophan-derived, indolic metabolites possess diverse functions in Arabidopsis innate immunity to microbial pathogen infection. Hers, we investigate the functional role and regulatory characteristics of indolic metabolism in Arabidopsis systemic acquired resistance （SAR） triggered by the bacterial pathogen Pseudomonas syringae. Indolic metabolism is broadly activated in both P. syringae-inoculated and distant, non-inoculated leaves. At inoculation sites, camalexin, indol-3-ylmethylamine （13A）, and indole-3-carboxylic acid （ICA） are the major accumulating compounds. Camalexin accumulation is positively affected by MYB122, and the cytochrome P450 genes CYP81F1 and CYP81F2. Local 13A production, by contrast, occurs via indole glucosinolate breakdown by PEN2- dependent and independent pathways. Moreover, exogenous application of the defense hormone salicylic acid stimulates 13A generation at the expense of its precursor indol-3-ylmethylglucosinolate （13M）, and the SAR regulator pipecolic acid primes plants for enhanced P. syringae-induced activation of distinct branches of indolic metabolism. In uninfected systemic tissue, the metabolic response is more specific and associated with enhanced levels of the indolics 13A, ICA, and indole-3-carbaldehyde （ICC）. Systemic indole accumulation fully depends on functional CYP79B2/3, PEN2, and MYB34/51/122, and requires functional SAR signaling. Genetic analyses suggest that systemi- cally elevated indoles are dispensable for SAR and associated systemic increases of salicylic acid. However, soil-grown but not hydroponically -cultivated cyp79b2/3 and pen2 plants, both defective in indolic secondary metabolism, exhibit pre-induced immunity, which abrogates their intrinsic ability to induce SAR.

Diclofop-methyl affects microbial rhizosphere community and induces systemic acquired resistance in rice

Diclofop-methyl（DM）,a widely used herbicide in food crops,may partly contaminate the soil surface of natural ecosystems in agricultural area and exert toxic effects at low dose to nontarget plants.Even though rhizosphere microorganisms strongly interact with root cells,little is known regarding their potential modulating effect on herbicide toxicity in plants.Here we exposed rice seedlings（Xiushui 63） to 100 μg/L DM for 2 to 8 days and studied the effects of DM on rice rhizosphere microorganisms,rice systemic acquired resistance（SAR） and rice-microorganisms interactions.The results of metagenomic 16 S rDNA Illumina tags show that DM increases bacterial biomass and affects their community structure in the rice rhizosphere.After DM treatment,the relative abundance of the bacterium genera Massilia and Anderseniella increased the most relative to the control.In parallel,malate and oxalate exudation by rice roots increased,potentially acting as a carbon source for several rhizosphere bacteria.Transcriptomic analyses suggest that DM induced SAR in rice seedlings through the salicylic acid（but not the jasmonic acid） signal pathway.This response to DM stress conferred resistance to infection by a pathogenic bacterium,but was not influenced by the presence of bacteria in the rhizosphere since SAR transcripts did not change significantly in xenic and axenic plant roots exposed to DM.The present study provides new insights on the response of rice and its associated microorganisms to DM stress.

Antibiotic resistance in patients with liver cirrhosis:Prevalence and current approach to tackle

Regardless of etiology,complications with bacterial infection in patients with cirrhosis are reported in the range of 25%-46%according to the most recent data.Due to frequent episodes of bacterial infection and repetitive antibiotic treatment,most often with broad-spectrum gram negative coverage,patients with cirrhosis are at increased risk of encountering multidrug resistant bacteria,and this raises concern.In such patients,extended-spectrum beta-lactamase and AmpCproducing Enterobacterales,methicillin-or vancomycin-resistant Staphylococcus aureus,vancomycin-resistant Enterococci,carbapenem-resistant Pseudomonas aeruginosa,and Acinetobacter baumannii,all of which are difficult to treat,are the most common.That is why novel approaches to the prophylaxis and treatment of bacterial infections to avoid antibiotic resistance have recently been developed.At the same time,our knowledge of resistance mechanisms is constantly updated.This review summarizes the current situation regarding the burden of antibiotic resistance,including the prevalence and mechanisms of intrinsic and acquired resistance in bacterial species that most frequently cause complications in patients with liver cirrhosis and recent developments on how to deal with multidrug resistant bacteria.

Mechanisms of acquired resistance to fibroblast growth factor receptor targeted therapy

Oncogenic activation of the fibroblast growth factor receptor(FGFR)through mutations and fusions of the FGFR gene occur in a variety of different malignancies such as urothelial carcinoma and cholangiocarcinoma.Inhibition of the kinase domain of the FGFR with targeted oral FGFR inhibitors has been shown in both preclinical and early phase clinical trials to lead to meaningful reductions in tumour size and larger confirmatory randomized trials are underway.Acquired resistance to FGFR inhibition using a variety of mechanisms that includes,activation of alternate signaling pathways and expansion of tumour clones with gatekeeper mutations in the FGFR gene.This review summarizes the acquired resistance mechanisms to FGFR therapy and therapeutic approaches to circumventing resistance.

Targeting apoptosis to manage acquired resistance to third generation EGFR inhibitors

A significant clinical challenge in lung cancer treatment is management of the inevitable acquired resistance to third-generation epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(EGFR-TKIs),such as osimertinib,which have shown remarkable success in the treatment of advanced NSCLC with EGFR activating mutations,in order to achieve maximal response duration or treatment remission.Apoptosis is a major type of programmed cell death tightly associated with cancer development and treatment.Evasion of apoptosis is considered a key hallmark of cancer and acquisition of apoptosis resistance is accordingly a key mechanism of drug acquired resistance in cancer therapy.It has been clearly shown that effective induction of apoptosis is a key mechanism for third generation EGFR-TKIs,particularly osimertinib,to exert their therapeutic efficacies and the development of resistance to apoptosis is tightly associated with the emergence of acquired resistance.Hence,restoration of cell sensitivity to undergo apoptosis using various means promises an effective strategy for the management of acquired resistance to third generation EGFR-TKIs.

A case report of response to crizotinib in chemotherapy-refractory metastatic gallbladder cancer with met amplification and acquired resistance resulting from the loss of MET amplification

Gallbladder cancer(GBC)is a highly invasive disease and the most prevalent malignancy of the biliary system.Patients with GBC are commonly diagnosed at a late stage and have an unfavorable prognosis.Palliative chemotherapy has been the standard care for recurrent or metastatic disease in the past decades.Recently,several targeted therapies have been investigated in advanced biliary tract cancer(BTC)including inhibitors of genes or pathways such as FGFR2 fusions or rearrangements,IDH1 mutations,and NTRK gene fusions.Also,several clinical studies involving molecular stratification have been performed in defined patient groups,for example,BRAF V600E and HER2.Mesenchymal epithelial transition(MET)encodes a tyrosine kinase receptor and its ligand hepatocyte growth factor is a proto-oncogene.Targeting the MET signaling pathway is an effective strategy in numerous cancer types.However,the poor efficacy of MET inhibitors has been demonstrated in several phase II studies,but currently no reports have explained the potential mechanisms of resistance to MET inhibitors in BTC.In this article,we report a case of metastatic GBC with MET amplification that exhibited a rapid response to crizotinib after the failure of two lines of chemotherapy.After the patient had progressed and discontinued crizotinib,cabozantinib was introduced.Analysis of circulating tumor DNA(ctDNA)by nextgeneration sequencing(NGS)indicated a loss of MET amplification status.To our knowledge,this is the first case study demonstrating the use of NGS in ctDNA to monitor the development of acquired resistance during anti-MET treatment in GBC.

T790M mutation in stage IV EGFR-mutated NSCLC patient with acquired resistance reverted to original 19Del mutation after administration of a series of precision treatments:a case report

Existing studies have yet to elucidate clearly the mechanisms of secondary resistance to third generation epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),neither is there any established standard therapy for patients resistant to third generation EGFR-TKIs.This case report demonstrates a rare mutation pattern in a male patient with a pathologic diagnosis of non-small cell lung cancer(NSCLC)harboring an EGFR exon 19 deletion(19Del)mutation,who then acquired an EGFR-T790M mutation after developing resistance to the first generation EGFR-TKI(gefitinib).The mutation reverted to the original EGFR-19Del mutation after the patient developed secondary resistance against the third generation TKI(osimertinib).This patient eventually achieved partial response(PR)with second generation TKI(afatinib)as a fourth-line treatment.

Drug-adapted cancer cell lines as preclinical models of acquired resistance

Acquired resistance formation limits the efficacy of anti-cancer therapies.Acquired and intrinsic resistance differ conceptually.Acquired resistance is the consequence of directed evolution,whereas intrinsic resistance depends on the(stochastic)presence of pre-existing resistance mechanisms.Preclinical model systems are needed to study acquired drug resistance because they enable:(1)in depth functional studies;(2)the investigation of non-standard treatments for a certain disease condition(which is necessary to identify small groups of responders);and(3)the comparison of multiple therapies in the same system.Hence,they complement data derived from clinical trials and clinical specimens,including liquid biopsies.Many groups have successfully used drug-adapted cancer cell lines to identify and elucidate clinically relevant resistance mechanisms to targeted and cytotoxic anti-cancer drugs.Hence,we argue that drug-adapted cancer cell lines represent a preclinical model system in their own right that is complementary to other preclinical model systems and clinical data.

Articulating beneficial rhizobacteria-mediated plant defenses through induced systemic resistance:A review

Induced systemic resistance(ISR)is a mechanism by which certain plant beneficial rhizobacteria and fungi produce immunity,which can stimulate crop growth and resilience against various phytopathogens,insects,and parasites.These beneficial rhizobacteria and fungi improve plant performance by regulating hormone signaling,including salicylic acid(SA),jasmonic acid(JA),prosystemin,pathogenesis-related gene 1,and ethylene(ET)pathways,which activate the gene expression of ISR,the synthesis of secondary metabolites,various enzymes,and volatile compounds that ultimately induce defense mechanisms in plant.To protect themselves from disease,plants have various advanced defense mechanisms in which local acquired resistance,systemic gene silencing,systemic wound response,systemic acquired resistance(SAR),and ISR are involved.Several rhizobacteria activate the SA-dependent SAR pathway by producing SA at the root’s surface.In contrast,other rhizobacteria can activate different signaling pathways independent of SA(SA-independent ISR pathways)such as those dependent on JA and ET signaling.The main objective of this review is to provide insight into the types of induced resistance utilized for plant defense.Further to this,the genetic approaches used to suppress disease-causing genes,i.e.,RNA interference and antisense RNA,which are still underutilized in sustainable agriculture,along with the current vision for virus-induced gene silencing are also discussed.

Effect of EGFR-TKI retreatment following chemotherapy for advanced non-small cell lung cancer patients who underwent EGFR-TKI

Objective： Non-small cell lung cancer （NSCLC） patients with epidermal growth factor receptor （EGFR）-activating mutations have higher response rate and more prolonged survival following treatment with single-agent EGFR tyrosine kinase inhibitor （EGFR-TKI） compared with patients with wild-type EGFR. However, all patients treated with reversible inhibitors develop acquired resistance over time. The mechanisms of resistance are complicated. The lack of established therapeutic options for patients after a failed EGFR-TKI treatment poses a great challenge to physicians in managing this group of lung cancer patients. This study evaluates the influence of EGFR-TKI retreatment following chemotherapy after failure of initial EGFR-TKI within at least 6 months on NSCLC patients. Methods： ＇i-he data of 27 patients who experienced treatment failure from their initial use of EGFR-TKI within at least 6 months were analyzed. After chemotherapy, the patients were retreated with EGFR-TKI （gefitinib 250 mg qd or erlotinib 150 mg qd）, and the tumor progression was observed. The patients were assessed for adverse events and response to therapy. Targeted tumor lesions were assessed with CT scan. Results： Of the 27 patients who received EGFR-TKI retreatment~ 1 （3.7%） patient was observed in complete response （CR）, 8 （29.6%） patients in partial response （PR）, 14 （51.9%） patients in stable disease （SD）, and 4 （14.8%） patients in progressive disease （PD）. The disease control rate （DCR） was 85.2% （95% CI： 62%-94%）. The median progression-free survival （mPFS） was 6 months （95% CI： 1-29）. Of the 13 patients who received the same EGFR-TKI, 1 patient in CR, 3 patients in PR, 8 patients in SD, and 2 patients in PD were observed. The DCRwas 84.6%, and the mPFS was 5 months. Of the 14 patients who received another EGFR-TKI, no patient in CR~ 6 patients in PR, 6 patients in SD, and 2 patients in PD were observed. The DCRwas 85.7%, and the mPFS was 9.5 months. Significant difference was found between the two groups in PFS but not in response rate or D CR. Conclusion： Retreatment of EGFR-TKIs can be considered an option after failure of chemotherapy for patients who were previously controlled by EGFR-TKI treatment.

Predicting and overcoming resistance to CDK9 inhibitors for cancer therapy

Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival.Targeting CDK9 has shown potent anti-tumor activity in clinical trials among different cancers.However,the study and knowledge on drug resistance to CDK9 inhibitors are very limited.In this study,we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor BAY1251152.Through genomic sequencing,we identified in the kinase domain of CDK9 a mutation L156F,which is also a coding SNP in the CDK9 gene.By knocking in L156F into cancer cells using CRISPR/Cas9,we found that single CDK9 L156F could drive the resistance to CDK9 inhibitors,not only ATP competitive inhibitor but also PROTAC degrader.Mechanistically,CDK9 L156F disrupts the binding with inhibitors due to steric hindrance,further,the mutation affects the thermal stability and catalytic activity of CDK9 protein.To overcome the drug resistance mediated by the CDK9-L156F mutation,we discovered a compound,IHMT-CDK9-36 which showed potent inhibition activity both for CDK9 WT and L156F mutant.Together,we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors.

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.

Emerging resistance vs. losing response to immune check point inhibitors in renal cell carcinoma: two differing phenomena

The introduction of immune checkpoint inhibitor (ICI) has revolutionized the treatment of metastatic renal cell carcinoma (mRCC) and has dramatically improved the outcomes of patients. The use of monotherapy or combinations of ICIs targeting PD-1/PD-L1 and CTLA-4, as well as the addition of ICIs with tyrosine kinase inhibitors, has significantly enhanced the overall survival of mRCC patients. Despite these promising results, there remains a subset of patients who either do not respond to treatment (primary resistance) or develop resistance to therapy over time (acquired resistance). Understanding the mechanisms underlying the development of resistance to ICI treatment is crucial in the management of mRCC, as they can be used to identify new targets for innovative therapeutic strategies. Currently, there is an unmet need to develop new predictive and prognostic biomarkers that can aid in the development of personalized treatment options for mRCC patients. In this review, we summarize several mechanisms of ICI resistance in RCC, including alterations in tumor microenvironment, upregulation of alternative immune checkpoint pathways, and genetic and epigenetic changes. Additionally, we highlight potential strategies that can be used to overcome resistance, such as combination therapy, targeted therapy, and immune modulation.