Potential Resistance Mechanisms Research Articles

Honey bee populations surviving Varroa destructor parasitism in Latin America and their mechanisms of resistance

The honey bee (Apis mellifera) parasitic mite, Varroa destructor, is considered one of the main causes of colony losses in European honey bee (EHB) populations around the world. However, some EHB and Africanized honey bee (AHB) populations (derived from the African subspecies A. m. scutellata) that inhabit tropical and subtropical regions of the Americas, have survived varroa mite infestations in the absence of acaricide treatments. It is conceivable to expect that these honey bee populations, which have been subjected to natural selection over decades, would have developed resistance against V. destructor or possess pre-existing adaptations that allow them to survive mite parasitism. Here, we present a comprehensive literature review describing the spread of V. destructor and the honey bee populations occurring in Latin America (LA), and summarize the evidence of resistance of those populations to V. destructor. We also analyze reports describing the potential mechanisms of mite resistance and how they operate in those honey bee populations. Studies of a few EHB, as well as of numerous AHB populations exhibiting resistance to V. destructor in LA, unveil the existence of evolutionary adaptations that restrain V. destructor population growth and provide insight into the current host-parasite relationship. This review supports the notion that selective breeding of local honey bee populations from LA could be a viable strategy to manage varroa mite infestations in colonies.

A novel mutation Trp-2027-Gly in acetyl-CoA carboxylase confers resistance to cyhalofop-butyl in Chinese sprangletop (Leptochloa chinensis).

Chinese sprangletop [Leptochloa chinensis (L.) Nees] control is threatened by resistance to acetyl-CoA carboxylase (ACCase)-inhibiting herbicides. In this study, a L. chinensis population, HFLJ18, that survived cyhalofop-butyl [aryloxyphenoxypropionate (APP) herbicide, CyB] treatment was collected from a rice field in Lujiang County, Anhui Province, China. This study aimed to evaluate the susceptibility of HFLJ18 to herbicides with different modes-of-action and investigate the potential mechanisms of resistance to CyB. The HFLJ18 population exhibited high levels of resistance to CyB (10.92-fold) and showed resistance to the ACCase inhibitors metamifop (4.63-fold) and fenoxaprop-P-ethyl (8.39-fold), but was susceptible to clethodim, pinoxaden, florpyrauxifen-benzyl, oxadiazon and pretilachlor. Target gene sequencing revealed a novel Trp-to-Gly substitution at codon position 2027 of ACCase in the resistant plants. Molecular docking revealed that the spatial structure of ACCase changed significantly following the substitution, as indicated by reduced H-bonds. A newly derived cleaved amplified polymorphic sequence (dCAPS) marker was subsequently developed to detect the Trp-2027-Gly mutation in the ACCase of L. chinensis. Additionally, pretreatment with the cytochrome P450 (P450) inhibitor piperonyl butoxide (PBO) and the glutathione S-transferase (GST) inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) did not reverse resistance to CyB, suggesting that nontarget-site resistance mechanisms were not involved in CyB resistance in the HFLJ18 population. Overall, the resistance to CyB in the HFLJ18 population derived from the mutation of ACCase gene, and to the best of our knowledge, this is the first report of the ACCase Trp-2027-Gly mutation conferring resistance to ACCase-inhibiting herbicides in grass species. © 2024 Society of Chemical Industry.

Research Progress on Physiological, Biochemical, and Molecular Mechanisms of Potato in Response to Drought and High Temperature

With the intensifying global warming trend, extreme heat and drought are becoming more frequent, seriously impacting potato yield and quality. To maintain sustainable potato production, it is necessary to breed new potato varieties that are adaptable to environmental changes and tolerant to adversity. Despite its importance, there is a significant gap in research focused on the potential mechanisms of potato resistance to abiotic stresses like drought and high temperatures. This article provides a comprehensive review of the recent research available in academic databases according to subject keywords about potato drought tolerance and high temperature tolerance with a view to providing an important theoretical basis for the study of potato stress mechanism and the selection and breeding of potato varieties with drought and high-temperature resistance. The suitable relative soil moisture content for potato growth and development is 55% to 85%, and the suitable temperature is 15 °C to 25 °C. The growth and development of potato plants under drought and high-temperature stress conditions are inhibited, and plant morphology is altered, which affects the process of potato stolon formation, tuberization and expansion, ultimately leading to a significant reduction in potato tuber yields and a remarkable degradation of the market grade of tubers, the specific gravity of tubers, and the processing quality of tubers. In addition, stress also adversely affects potato physiological and biochemical characteristics, such as reduction in root diameter and leaf area, decrease in net photosynthetic rate of leaves, production of reactive oxygen species (ROS), and increase in membrane lipid peroxidation. In addition, various types of genes and transcription factors are involved in the response to drought and heat at the molecular level in potato. This paper illustrates the effects of stress on potato growth and development and the molecular mechanisms of potato response to adversity in detail, which is intended to reduce the damage caused by drought and high temperature to potato in the context of global warming and frequent occurrence of extreme weather to ensure potato yield and quality and to further safeguard food security.

PD-L1 induces autophagy and primary resistance to EGFR–TKIs in EGFR-mutant lung adenocarcinoma via the MAPK signaling pathway

Resistance to epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs) is a significant cause of treatment failure and cancer recurrence in non-small cell lung cancer (NSCLC). Approximately 30% of patients with EGFR-activating mutations exhibit primary resistance to EGFR–TKIs. However, the potential mechanisms of primary resistance to EGFR–TKIs remain poorly understood. Recent studies have shown that increased expression of programmed death ligand-1 (PD-L1) is associated with EGFR–TKIs resistance. Therefore, the present study aimed to investigate the mechanism of PD-L1 in primary resistance to EGFR–TKIs in EGFR-mutant lung adenocarcinoma (LUAD) cells. We found that PD-L1 was associated with poor prognosis in patients with EGFR-mutant LUAD, while the combination of EGFR–TKIs with chemotherapy could improve its therapeutic efficacy. In vitro and in vivo experiments revealed that PD-L1 promoted the proliferation and autophagy and inhibited the apoptosis of LUAD cells. Mechanistic studies demonstrated that upregulation of PD-L1 was critical in inducing autophagy through the mitogen-activated protein kinase (MAPK) signaling pathway, which was beneficial for tumor progression and the development of gefitinib resistance. Furthermore, we found that gefitinib combined with pemetrexed could synergistically enhance antitumor efficacy in PD-L1-overexpression LUAD cells. Overall, our study demonstrated that PD-L1 contributed to primary resistance to EGFR–TKIs in EGFR-mutant LUAD cells, which may be mediated by inducing autophagy via the MAPK signaling pathway. These findings not only help improve the prognosis of patients with EGFR-mutant LUAD but also provide a reference for the research of other cancer types.

Reassessment of the genetic basis of natural rifampin resistance in the genus Rickettsia.

Rickettsia, a genus of obligate intracellular bacteria, includes species that cause significant human diseases. This study challenges previous claims that the Leucine-973 residue in the RNA polymerase beta subunit is the primary determinant of rifampin resistance in Rickettsia. We investigated a previously untested Rickettsia species, R. lusitaniae, from the Transitional group and found it susceptible to rifampin, despite possessing the Leu-973 residue. Interestingly, we observed the conservation of this residue in several rifampin-susceptible species across most Rickettsia phylogenetic groups. Comparative genomics revealed potential alternative resistance mechanisms, including additional amino acid variants that could hinder rifampin binding and genes that could facilitate rifampin detoxification through efflux pumps. Importantly, the evolutionary history of Rickettsia genomes indicates that the emergence of natural rifampin resistance is phylogenetically constrained within the genus, originating from ancient genetic features shared among a unique set of closely related Rickettsia species. Phylogenetic patterns appear to be the most reliable predictors of natural rifampin resistance, which is confined to a distinct monophyletic subclade known as Massiliae. The distinctive features of the RNA polymerase beta subunit in certain untested Rickettsia species suggest that R. raoultii, R. amblyommatis, R. gravesii, and R. kotlanii may also be naturally rifampin-resistant species.

In vitro resistance development gives insights into molecular resistance mechanisms against cefiderocol.

Cefiderocol, a novel siderophore cephalosporin, demonstrates promising in vitro activity against multidrug-resistant Gram-negative bacteria, including carbapenemase-producing strains. Nonetheless, only a few reports are available regarding the acquisition of resistance in clinical settings, primarily due to its recent usage. This study aimed to investigate cefiderocol resistance using an in vitro resistance development model to gain insights into the underlying molecular resistance mechanisms. Cefiderocol susceptible reference strains (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa) and a clinical Acinetobacter baumannii complex isolate were exposed to increasing cefiderocol concentrations using a high-throughput resistance development model. Cefiderocol susceptibility testing was performed using broth microdilution. Whole-genome sequencing was employed to identify newly acquired resistance mutations. Our in vitro resistance development model led to several clones of strains exhibiting cefiderocol resistance, with MIC values 8-fold to 512-fold higher than initial levels. In total, we found 42 different mutations in 26 genes, of which 35 could be described for the first time. Putative loss-of-function mutations were detected in the envZ, tonB, and cirA genes in 13 out of 17 isolates, leading to a decrease in cefiderocol influx. Other potential resistance mechanisms included multidrug efflux pumps (baeS, czcS, nalC), antibiotic-inactivating enzymes (ampR, dacB), and target mutations in penicillin-binding-protein genes (mrcB). This study reveals new insights into underlying molecular resistance mechanisms against cefiderocol. While mutations leading to reduced influx via iron transporters was the most frequent resistance mechanism, we also detected several other novel resistance mutations causing cefiderocol resistance.

Insights into response of seagrass (Zostera marina) to sulfide exposure at morphological, physiochemical and molecular levels in context of coastal eutrophication and warming.

Sulfide in sediment porewaters, is toxic to rooted macrophytes in both marine and freshwater environments. Current research on sulfide stress in seagrasses primarily focuses on morphological and physiological aspects, with little known about the molecular response and resistance mechanisms. This study first investigated the damage caused by sulfide to eelgrass (Zostera marina L.) using transcriptomic, metabolomic, and other physiological and biochemical indicators and explored the potential resistance of eelgrass at molecular level through laboratory simulated and in-situ sulfide stress experiments. Comprehensive results showed that sulfide stress severely inhibited the growth, photosynthesis, and antioxidant enzyme activities of eelgrass. Importantly, transcriptome analysis revealed significant activation of pathways related to carbohydrate and sulfur metabolism. This activation served a dual purpose: providing an energy source for eelgrass stress response and achieving detoxification through accelerated sulfur metabolism-a potential resistance mechanism. The toxicity of sulfide increased with rising temperature as evidenced by a decrease in EC50. Results from recovery experiments indicated that when Fv/Fm reduced to about 0 under sulfide stress, the growth and photosynthesis of eelgrass recovered to normal level after timely removal of sulfide. However, prolonged exposure to sulfide resulted in failure to recover, leading ultimately to plant death. This study not only enhances our understanding of the molecular-level impacts of sulfide on seagrasses but also provides guidance for the management and ecological restoration of seagrass meadows under sulfide stress.

Genotypic Variation and Potential Mechanisms of Resistance against Multiple Insect Herbivores in Cranberries.

Plant genotypes often exhibit varying resistance levels to herbivores. However, the impact of this genotypic variation on resistance against multiple herbivores remains poorly understood, especially in crops undergoing recent process of domestication. To address this gap, we studied the magnitude and mechanism of resistance in 12 cranberry (Vaccinium macrocarpon) genotypes to three leaf-chewing herbivores - Sparganothis fruitworm (Sparganothis sulfureana), spotted fireworm (Choristoneura parallela), and spongy moth (Lymantria dispar) - along a domestication gradient (native 'wild' genotypes, 'early hybrid' genotypes, and 'modern hybrid' genotypes). Like cranberries, S. sulfureana and C. parallela are native to the United Sates, while L. dispar is an invasive pest. We measured the survival and growth of larvae on each genotype, as well as variation in plant performance (height and biomass) and leaf defensive chemical traits (C/N ratio, total phenolics, total proanthocyanidins, and flavonols levels) in these genotypes to elucidate potential resistance mechanisms. We found differences in C. parallela and L. dispar larval performance across genotypes, with larvae performing better on the modern hybrid genotypes, while S. sulfureana showed no differences. Morphological and chemical traits varied among genotypes, with total phenolics being the only trait correlated with C. parallela and L. dispar larval performance. Notably, the wild genotypes 'McFarlin' and 'Potter' had higher total phenolics and were more resistant to both herbivores than the modern hybrids 'Demoranville' and 'Mullica Queen.' This research contributes to a comprehensive understanding of the impact of crop domestication on multiple insect herbivores, offering insights for future breeding efforts to enhance host-plant resistance against agricultural pests.

Sterol 14-alpha demethylase (CYP51) activity in Leishmania donovani is likely dependent upon cytochrome P450 reductase 1.

Liposomal amphotericin B is an important frontline drug for the treatment of visceral leishmaniasis, a neglected disease of poverty. The mechanism of action of amphotericin B (AmB) is thought to involve interaction with ergosterol and other ergostane sterols, resulting in disruption of the integrity and key functions of the plasma membrane. Emergence of clinically refractory isolates of L. donovani and L. infantum is an ongoing issue and knowledge of potential resistance mechanisms can help to alleviate this problem. Here we report the characterisation of four independently selected L. donovani clones that are resistant to AmB. Whole genome sequencing revealed that in three of the moderately resistant clones, resistance was due solely to the deletion of a gene encoding C24-sterol methyltransferase (SMT1). The fourth, hyper-resistant resistant clone (>60-fold) was found to have a 24 bp deletion in both alleles of a gene encoding a putative cytochrome P450 reductase (P450R1). Metabolic profiling indicated these parasites were virtually devoid of ergosterol (0.2% versus 18% of total sterols in wild-type) and had a marked accumulation of 14-methylfecosterol (75% versus 0.1% of total sterols in wild-type) and other 14-alpha methylcholestanes. These are substrates for sterol 14-alpha demethylase (CYP51) suggesting that this enzyme may be a bona fide P450R specifically involved in electron transfer from NADPH to CYP51 during catalysis. Deletion of P450R1 in wild-type cells phenocopied the metabolic changes observed in our AmB hyper-resistant clone as well as in CYP51 nulls. Likewise, addition of a wild type P450R1 gene restored sterol profiles to wild type. Our studies indicate that P450R1 is essential for L. donovani amastigote viability, thus loss of this gene is unlikely to be a driver of clinical resistance. Nevertheless, investigating the mechanisms underpinning AmB resistance in these cells provided insights that refine our understanding of the L. donovani sterol biosynthetic pathway.

Establishment of a trastuzumab-resistant extramammary Paget disease model: loss of PTEN as a potential mechanism.

Extramammary Paget disease (EMPD) is a rare, cutaneous intraepithelial adenocarcinoma typically treated with wide local excision. Unfortunately, a number of patients with metastases show poor responses to chemotherapy. While some studies have explored trastuzumab's effectiveness against EMPD positive for human epidermal growth factor receptor 2 (HER2), trastuzumab resistance (TR) may emerge after anti-HER2 therapy. In this study, we established TR EMPD patient-derived xenografts (PDX) that replicated the histological and HER2 expression traits of naive EMPD tumours. Cancer gene analyses revealed a loss of the PTEN gene in TR tumours, which was further confirmed by immunohistochemical staining and immunoblotting to test for protein expression levels. Reduced PTEN levels correlated with increased protein kinase B (Akt) phosphorylation and p27 downregulation, suggesting a potential mechanism for trastuzumab resistance in EMPD cells. In the trastuzumab-sensitive EMPD-PDX mouse model, PTEN inhibitors partially restored trastuzumab-mediated tumour regression. The TR EMPD-PDX responded favourably to targeted therapy (lapatinib, abemaciclib, palbociclib) and chemotherapy (eribulin, docetaxel, trastuzumab deruxtecan). This study demonstrates an innovative TR EMPD-PDX model and introduces promising antineoplastic effects with various treatments for TR EMPD tumours.

Secondary Analysis of Human Bulk RNA-Seq Dataset Suggests Potential Mechanisms for Letrozole Resistance in Estrogen-Positive (ER+) Breast Cancer

Secondary Analysis of Human Bulk RNA-Seq Dataset Suggests Potential Mechanisms for Letrozole Resistance in Estrogen-Positive (ER+) Breast Cancer

Secondary Analysis of Human Bulk RNA-Seq Dataset Suggests Potential Mechanisms for Letrozole Resistance in Estrogen-Positive (ER+) Breast Cancer.

Estrogen receptor-positive (ER+) breast cancer is common among postmenopausal women and is frequently treated with Letrozole, which inhibits aromatase from synthesizing estrogen from androgens. Decreased estrogen slows the growth of tumors and can be an effective treatment. The increase in Letrozole resistance poses a unique problem for patients. To better understand the underlying molecular mechanism(s) of Letrozole resistance, we reanalyzed transcriptomic data by comparing individuals who responded to Letrozole therapy (responders) to those who were resistant to treatment (non-responders). We identified SOX11 and S100A9 as two significant differentially expressed genes (DEGs) between these patient cohorts, with "PLK1 signaling events" being the most significant signaling pathway. We also identified PRDX4 and E2F8 gene products as being the top mechanistic transcriptional markers for ER+ treatment resistance. Many of the significant DEGs that we identified play a known role in ER+ breast cancer or other types of cancer, which partially validate our results. Several of the gene products we identified are novel in the context of ER+ breast cancer. Many of the genes that we identified warrant further research to elucidate the more specific molecular mechanisms of Letrozole resistance in this patient population and could potentially be used as prognostic markers with further wet lab validation. We anticipate that these findings could contribute to improved detection and therapeutic outcomes in aromatase-resistant ER+ breast cancer patients.

Tetraniliprole resistance in field-collected populations of Tuta absoluta (Lepidoptera: Gelechiidae) from China: Baseline susceptibility, cross-resistance, inheritance, and biochemical mechanism

Tuta absoluta is one of the most destructive and invasive insect pests throughout the world. It feeds on numerous solanaceous plant species and has developed resistance to most types of popular insecticides. Tetraniliprole is a novel diamide chemical agent that acts as a modulator of the ryanodine receptor. To establish T. absoluta susceptibility to tetraniliprole and to understand potential mechanisms of resistance, we monitored 18 field populations of T. absoluta collected from northern China. One field-evolved resistant population, Huailai (HL), showed moderate resistance to tetraniliprole (36.2-fold) in comparison with susceptible strain YN-S. Assays of cross-resistance, synergism, metabolic enzyme activity, and inheritance of resistance were performed with YN-S strain and HL population. The latter displayed 12.2- and 6.7-fold cross-resistance to chlorantraniliprole and flubendiamide, respectively, but little cross-resistance to broflanilide (1.6-fold), spinosad (2.1-fold), metaflumizone (1.5-fold), or indoxacarb (2.8-fold). Genetic analyses revealed that tetraniliprole resistance in HL population was autosomal, incompletely dominant, and polygenic. Piperonyl butoxide was found to significantly increase tetraniliprole toxicity, and enzymatic activities of P450 monooxygenase and glutathione S-transferase were significantly higher in HL than YN-S population. These results enhance our knowledge of the inheritance and mechanism of tetraniliprole resistance, enabling future optimization of resistance management strategies.

Exploring behavioural and physiological adaptations in mountain pine beetle in response to elevated ozone concentrations

Elevated ozone (eO3) concentrations pose a threat to insect populations by potentially altering their behaviour and physiology. This study investigates the effects of eO3 concentrations on the mountain pine beetle which is a major tree-killing species of conifers in northwestern North America. We are particularly interested in understanding the effects of eO3 concentrations on beetle behaviour and physiology and possible transgenerational impacts on bark beetle broods. We conducted O3-enrichment experiments in a controlled laboratory setting using different O3 concentrations (100–200 ppb; projected for 2050–2100) and assessed various beetle responses, including CO2 respiration, mating behaviour, survival probability, locomotion, and attraction behaviour. Transgenerational impacts on the first and second generations were also analyzed by studying brood morphology, mating behaviour, survival, and pheromone production. We found that beetles exposed to eO3 concentrations had shorter oviposition galleries and reduced brood production. Beetle pheromones were also degraded by eO3 exposure. However, exposure to eO3 also prompted various adaptive responses in beetles. Despite reduced respiration, eO3 improved locomotor activity and the olfactory response of beetles. Surprisingly, beetle survival probability was also improved both in the parents and their broods. We also observed transgenerational plasticity in the broods of eO3-exposed parents, suggesting potential stress resistance mechanisms. This was evident by similar mating success, oviposition gallery length, and brood numbers produced in both control and eO3 concentration treatments. This study demonstrates the sensitivity of mountain pine beetles to increased O3 concentrations, contributing crucial insights into the ecological implications of eO3 concentrations on their populations. Overall, the outcome of this study contributes to informed climate change mitigation strategies and adaptive management practices for the development of resilient forests in response to emerging forest insect pests worldwide.

Tetraniliprole resistance in field-collected populations of Tuta absoluta (Lepidoptera: Gelechiidae) from China: Baseline susceptibility, cross-resistance, inheritance, and biochemical mechanism

Tuta absoluta is one of the most destructive and invasive insect pests throughout the world. It feeds on numerous solanaceous plant species and has developed resistance to most types of popular insecticides. Tetraniliprole is a novel diamide chemical agent that acts as a modulator of the ryanodine receptor. To establish T. absoluta susceptibility to tetraniliprole and to understand potential mechanisms of resistance, we monitored 18 field populations of T. absoluta collected from northern China. One field-evolved resistant population, Huailai (HL), showed moderate resistance to tetraniliprole (36.2-fold) in comparison with susceptible strain YN-S. Assays of cross-resistance, synergism, metabolic enzyme activity, and inheritance of resistance were performed with YN-S strain and HL population. The latter displayed 12.2- and 6.7-fold cross-resistance to chlorantraniliprole and flubendiamide, respectively, but little cross-resistance to broflanilide (1.6-fold), spinosad (2.1-fold), metaflumizone (1.5-fold), or indoxacarb (2.8-fold). Genetic analyses revealed that tetraniliprole resistance in HL population was autosomal, incompletely dominant, and polygenic. Piperonyl butoxide was found to significantly increase tetraniliprole toxicity, and enzymatic activities of P450 monooxygenase and glutathione S-transferase were significantly higher in HL than YN-S population. These results enhance our knowledge of the inheritance and mechanism of tetraniliprole resistance, enabling future optimization of resistance management strategies.

An open-label, phase 1, multicenter study to evaluate the safety and preliminary anti-tumor activity of NT-112 in human leukocyte antigen-C*08:02–positive adult patients with unresectable, advanced, and/or metastatic solid tumors that are positive for the KRAS G12D mutation.

TPS2677 Background: The landscape of cancer treatment is evolving with the emergence of innovative immunotherapies. Among these, T cell receptor-engineered T cell (TCR-T) therapy has shown promise for patients with solid tumor malignancies. Targeting driver mutations, such as KRAS, may offer novel therapeutic options for patients with limited treatment options. Oncogenic driver mutations in KRAS typically involve single-base mutations at genomic hotspot locations. The KRAS isoform is mutated in 84% of RAS-driven cancers and in nearly 100% of pancreatic ductal adenocarcinoma (PDAC). The KRAS G12D mutation is the most frequent mutation in PDAC (28%), followed by colorectal cancers (12%). Despite its well-established target role in tumorigenesis, there is no FDA-approved therapy targeting the G12D variant. NT-112 is an autologous TCR-T cell therapy targeting the KRAS G12D mutation presented by HLA-C*08:02, armored by disruption of the gene encoding the transforming growth factor beta receptor type 2 (TGFBR2) in order to reduce the immunosuppressive effect of TGF-β in the tumor microenvironment. Methods: This first-in-human, open label, multicenter, Phase 1, dose escalation study aims to assess the safety, identify the MTD and evaluate potential anti-tumor activities of NT-112 in subjects with solid tumors. The study will enroll up to 24 adult subjects harboring the KRAS G12D mutation that are HLA-C*08:02 positive, who exhibit progressive or recurrent disease after at least one line of standard of care treatment. Enrolled patients will undergo leukapheresis, from which, CD4 and CD8 T cells will be enriched and activated ex vivo. The genes encoding the TGFBR2 and the endogenous TCR α and β chains are knocked out from the activated T cells utilizing clustered regularly interspaced short palindromic repeats (CRISPR-Cas9). The HLA-C*08:02-restricted TCR specific to the KRAS G12D mutation is knocked-in in the TCR α locus. Subjects will undergo standard lymphodepletion followed by a single infusion of NT-112 and concurrent, daily, subcutaneous, recombinant IL-2 for up to 8 days. Dose escalation will occur across 3 ascending dose levels following the BOIN design. Subjects will be monitored for dose-limiting toxicities for 28 days following NT-112 infusion. Disease response will be assessed according to the RECIST v1.1 criteria. Comprehensive translational analysis will be conducted to gain insights into the mechanism of action, biomarkers associated with treatment response, and potential mechanisms of resistance. All subjects will be followed for up to 15 years. Clinical trial information: NCT06218914 .

Multi‐omics molecular phenotyping reveals the potential mechanisms of chemotherapy response and resistance in small cell lung cancer

Multi‐omics molecular phenotyping reveals the potential mechanisms of chemotherapy response and resistance in small cell lung cancer

Advances in CAR-NK cell therapy for lung cancer: is it a better choice in the future?

Lung cancer remains one of the leading causes of cancer-related mortality worldwide necessitating the development of innovative therapeutic strategies. Chimeric antigen receptor (CAR) natural killer (NK) cell therapy represents a promising advancement in the field of oncology offering a novel approach to target and eliminate tumor cells with high specificity and reduced risk of immune-related adverse effects. This paper reviews the mechanism, potential targets, and recent advances in CAR-NK cell therapy for lung cancer, including the design and engineering of CAR-NK cells, preclinical studies, and the outcomes of early-phase clinical trials. We highlight the unique advantages of using NK cells, such as their innate ability to recognize and kill cancer cells and their reduced potential for inducing graft-versus-host disease (GvHD) and cytokine release syndrome (CRS) compared to CAR T-cell therapies. Results from recent studies demonstrate significant antitumor activity in lung cancer models with improved targeting and persistence of CAR-NK cells observed in vitro and in vivo. Finally, we discuss the challenges in optimizing CAR-NK cell therapies, including the potential resistance mechanisms. The paper concludes with an outlook on the future directions of CAR-NK cell research and its implications for lung cancer treatment emphasizing the importance of continued innovation and collaboration in the field.

Acquired resistance to immunotherapy and chemoradiation in MYC amplified head and neck cancer

The proto-oncogene MYC encodes a nuclear transcription factor that has an important role in a variety of cellular processes, such as cell cycle progression, proliferation, metabolism, adhesion, apoptosis, and therapeutic resistance. MYC amplification is consistently observed in aggressive forms of several solid malignancies and correlates with poor prognosis and distant metastases. While the tumorigenic effects of MYC in patients with head and neck squamous cell carcinoma (HNSCC) are well known, the molecular mechanisms by which the amplification of this gene may confer treatment resistance, especially to immune checkpoint inhibitors, remains under-investigated. Here we present a unique case of a patient with recurrent/metastatic (R/M) HNSCC who, despite initial response to nivolumab-based treatment, developed rapidly progressive metastatic disease after the acquisition of MYC amplification. We conducted comparative transcriptomic analysis of this patient’s tumor at baseline and upon progression to interrogate potential molecular processes through which MYC may confer resistance to immunotherapy and/or chemoradiation and used TCGA-HNSC dataset and an institutional cohort to further explore clinicopathologic features and key molecular networks associated with MYC amplification in HNSCC. This study highlights MYC amplification as a potential mechanism of immune checkpoint inhibitor resistance and suggest its use as a predictive biomarker and potential therapeutic target in R/M HNSCC.

Unraveling resistance mechanisms in anti-CD19 chimeric antigen receptor-T therapy for B-ALL: a novel in vitro model and insights into target antigen dynamics

BackgroundCellular immunotherapy, represented by the chimeric antigen receptor T cell (CAR-T), has exhibited high response rates, durable remission, and safety in vitro and in clinical trials. Unfortunately, anti-CD19 CAR-T (CART-19) treatment alone is prone to relapse and has a particularly poor prognosis in relapsed/refractory (r/r) B-ALL patients. To date, addressing or reducing relapse remains one of the research priorities to achieve broad clinical application.MethodsWe manufactured second generation CART-19 cells and validated their efficacy and safety in vitro and in vivo. Through co-culture of Nalm-6 cells with short-term cultured CART-19 cells, CD19-negative Nalm-6 cells were detected by flow cytometry, and further investigation of the relapsed cells and their resistance mechanisms was evaluated in vitro.ResultsIn this study, we demonstrated that CART-19 cells had enhanced and specific antileukemic activities, and the survival of B-ALL mouse models after CART-19 treatment was significantly prolonged. We then shortened the culture time and applied the serum-free culture to expand CAR-T cells, followed by co-culturing CART-19 cells with Nalm-6 cells. Surprisingly, we observed the proliferation of CD19-negative Nalm-6 cells around 28 days. Identification of potential resistance mechanisms showed that the relapsed cells express truncated CD19 proteins with decreased levels and, more importantly, CAR expression was detected on the relapsed cell surface, which may ultimately keep them antigen-negative. Furthermore, it was validated that CART-22 and tandem CART-22/19 cells could effectively kill the relapsed cells, but neither could completely eradicate them.ConclusionsWe successfully generated CART-19 cells and obtained a CD19-negative refractory relapsed B-ALL cell line, providing new insights into the underlying mechanisms of resistance and a new in vitro model for the treatment of r/r B-ALL patients with low antigen density.