Development Of Drug Resistance Research Articles

BH3-mimetics or DNA-damaging agents in combination with RG7388 overcome p53 mutation-induced resistance to MDM2 inhibition.

The development of drug resistance reduces the efficacy of cancer therapy. Tumor cells can acquire resistance to MDM2 inhibitors, which are currently under clinical evaluation. We generated RG7388-resistant neuroblastoma cells, which became more proliferative and metabolically active and were less sensitive to DNA-damaging agents in vitro and in vivo, compared with wild-type cells. The resistance was associated with a mutation of the p53 protein (His193Arg). This mutation abated its transcriptional activity via destabilization of the tetrameric p53-DNA complex and was observed in many cancer types. Finally, we found that Cisplatin and various BH3-mimetics could enhance RG7388-mediated apoptosis in RG7388-resistant neuroblastoma cells, thereby partially overcoming resistance to MDM2 inhibition.

Small HBV surface antigendrives regorafenib resistance in HCC via KIAA1429-dependent m6A modification of CCR9.

A substantial body of literature, including our own, points to a connection between hepatitis B virus (HBV) infection and the development of drug resistance in hepatocellular carcinoma (HCC), particularly against sorafenib. However, the influence of HBV on resistance to regorafenib, another therapeutic agent, has been less studied. In this study, we used the GEO database (GSE87630) and clinical samples to demonstrate that C-C motif chemokine receptor 9 (CCR9) was highly expressed in HBV-related HCC and predicted poor overall survival. Its overexpression correlated with HBsAg-positive HCC patients. Both univariate and multivariable Cox regression analysis elucidated CCR9 was an independent risk factor for poor overall survival in HCC patients. Our in vitro findings further revealed that HBV structural proteins, small HBV surface antigen (SHBs), triggered an upregulation of CCR9. Functional assays showed that SHBs enhanced HCC cell proliferation, migration, and invasion, increased ABCB1 and ABCC1 expression, and promoted regorafenib resistance via CCR9. Intriguingly, overexpression of HBV plasmid and an AAV-HBV mouse model both exhibited a significant elevation in global N6-methyladenosine (m6A) levels. Further investigations revealed that SHBs elevated these m6A levels, upregulated CCR9 and stabilized CCR9 mRNA through KIAA1429-mediated m6A modification, with sites 1373 and 1496 on CCR9 mRNA being critical for modification. In conclusion, SHBs promoted HCC progression and regorafenib resistance via KIAA1429-mediatedm6A modification of CCR9. Our findings suggested that CCR9 could be a potential prognostic biomarker and a valuable molecular therapeutic target of regorafenib resistance in HBV-related HCC.

Elucidating the Role of Pro-renin Receptors in Pancreatic Ductal Adenocarcinoma Progression: A Novel Therapeutic Target in Cancer Therapy.

Pancreatic cancer is a highly aggressive malignancy with a very poor prognosis. The 5- year survival in these patients is very low, and most patients develop drug resistance to current therapies, so additional studies are needed to identify the potential role of new drug targets for the treatment of pancreatic cancer. Recent investigations have been performed regarding the roles of pro-renin receptors (PRR) in the initiation and development of cancers. PRR is a component of the local renin-angiotensin system (RAS). Local tissue RAS has been known in diverse organ systems, including the pancreas. Various investigations have implicated that PRRs are associated with the upregulation of various signaling pathways, like the renin-angiotensin system pathway, PI3K/Akt/mTOR, and the Wnt-signaling pathways, to contribute to pathological conditions, including cancer. In this review, we presented an overview of the role of PRR in the progression of pancreatic adenocarcinoma.

Step-wise evolution of azole resistance through copy number variation followed by KSR1 loss of heterozygosity in Candida albicans.

Antimicrobial drug resistance poses a global health threat, requiring a deeper understanding of the evolutionary processes that lead to its emergence in pathogens. Complex evolutionary dynamics involve multiple mutations that can result in cooperative or competitive (clonal interference) effects. Candida albicans, a major fungal pathogen, displays high rates of copy number variation (CNV) and loss of heterozygosity (LOH). CNV and LOH events involve large numbers of genes and could synergize during evolutionary adaptation. Understanding the contributions of CNV and LOH to antifungal drug adaptation is challenging, especially in the context of whole-population genome sequencing. Here, we document the sequential evolution of fluconazole tolerance and then resistance in a C. albicans isolate involving an initial CNV on chromosome 4, followed by an LOH on chromosome R that involves KSR1. Similar LOH events involving KSR1, which encodes a reductase in the sphingolipid biosynthesis pathway, were also detected in independently evolved fluconazole resistant isolates. We dissect the specific KSR1 codons that affect fluconazole resistance and tolerance. The combination of the chromosome 4 CNV and KSR1 LOH results in a >500-fold decrease in azole susceptibility relative to the progenitor, illustrating a compelling example of rapid, yet step-wise, interplay between CNV and LOH in drug resistance evolution.

Antifungal mechanism of nanosilver biosynthesized with Trichoderma longibrachiatum and its potential to control muskmelon Fusarium wilt.

Fusarium oxysporum (Schl.) f.sp. melonis, which causes muskmelon wilt disease, is a destructive filamentous fungal pathogen, attracting more attention to the search for effective fungicides against this pathogen. In particular, Silver nanoparticles (AgNPs) have strong antimicrobial properties and they are not easy to develop drug resistance, which provides new ideas for the prevention and control of muskmelon Fusarium wilt (MFW). This paper studied the effects of AgNPs on the growth and development of muskmelon, the control efficacy on Fusarium wilt of muskmelon and the antifungal mechanism of AgNPs to F. oxysporum. The results showed that AgNPs could inhibit the growth of F. oxysporum on the PDA and in the PDB medium at 100-200mg/L and the low concentration of 25mg/L AgNPs could promote the seed germination and growth of muskmelon seedlings and reduce the incidence of muskmelon Fusarium wilt. Further studies on the antifungal mechanism showed that AgNPs could impair the development, damage cell structure, and interrupt cellular metabolism pathways of this fungus. TEM observation revealed that AgNPs treatment led to damage to the cell wall and membrane and accumulation of vacuoles and vessels, causing the leakage of intracellular contents. AgNPs treatment significantly hampered the growth of mycelia in the PDB medium, even causing a decrease in biomass. Biochemical properties showed that AgNPs treatment stimulated the generation of reactive oxygen species (ROS) in 6h, subsequently producing malondialdehyde (MDA) and increasing protective enzyme activity. After 6h, the protective enzyme activity decreased. These results indicated that AgNPs destroy the cell structure and affect the metabolisms, eventually leading to the death of fungus.

Mechanistic Insights into Cisplatin Response in Breast Tumors: Molecular Determinants and Drug/Nanotechnology-Based Therapeutic Opportunities.

Breast cancer continues to be a major global health challenge, driving the need for effective therapeutic strategies. Cisplatin, a powerful chemotherapeutic agent, is widely used in breast cancer treatment. However, its effectiveness is often limited by systemic toxicity and the development of drug resistance. This review examines the molecular factors that influence cisplatin response and resistance, offering crucial insights for the scientific community. It highlights the significance of understanding cisplatin resistance's genetic and epigenetic contributors, which could lead to more personalized treatment approaches. Additionally, the review explores innovative strategies to counteract cisplatin resistance, including combination therapies, nanoparticle-based drug delivery systems, and targeted therapies. These approaches are under intensive investigation and promise to enhance breast cancer treatment outcomes. This comprehensive discussion is a valuable resource to advance breast cancer therapeutics and address the challenge of cisplatin resistance.

CCT3/ACTN4/TFRC axis protects hepatocellular carcinoma cells from ferroptosis by inhibiting iron endocytosis.

Sorafenib is widely used in treating advanced hepatocellular carcinoma (HCC). However, its effectiveness in prolonging patient survival is limited by the development of drug resistance. To systematically investigate the resistance mechanisms of Sorafenib, an integrative analysis combining posttranslational modification (PTM) omics and CRISPR/Cas9 knockout library screening was conducted. This analysis identified ubiquitination at lysine 21 (K21) on chaperonin-containing TCP1 subunit 3 (CCT3) as being associated with Sorafenib resistance. Transcriptomic data from HCC patients treated with Sorafenib revealed that CCT3 expression was lower in responders compared to non-responders. Experimentally, inhibiting the expression of CCT3 sensitized HCC cells to Sorafenib and enhanced Sorafenib-induced ferroptosis. Additionally, CCT3 was found to interact with ACTN4, hindering the recycling of transferrin receptor protein 1 (TFRC) to the cell membrane, thus obstructing iron endocytosis. Mechanistically, the inhibition of ferroptosis by CCT3 depends on the deubiquitination of K6-linked non-degradative ubiquitination at its K21, which occurs upon Sorafenib treatment. Moreover, CCT3 knockdown enhanced the anti-tumor effects of Sorafenib in nude mice. In summary, we have identified a novel function of the chaperone protein. Targeting the CCT3/ACTN4/TFRC axis offers a promising strategy to enhance ferroptosis and overcome Sorafenib resistance in HCC.

Bithionol eliminates acute myeloid leukaemia stem-like cells by suppressing NF-κB signalling and inducing oxidative stress, leading to apoptosis and ferroptosis.

Acute myeloid leukaemia (AML) is a lethal bone marrow neoplasm caused by genetic alterations in blood cell progenitors. Leukaemic stem cells (LSCs) are responsible for the development of AML, drug resistance and relapse. Bithionol is an old anthelmintic drug with potential antibacterial, antiviral, antifungal, anti-Alzheimer, and antitumour properties. In this work, we focused on the anti-AML LSC properties of bithionol. This compound inhibited the viability of both solid and haematological cancer cells, suppressed AML stem-like cells, and inhibited AML growth in NSG mice at a dosage of 50 mg/kg, with tolerable systemic toxicity. Bithionol significantly reduced the levels of phospho-NF-κB p65 (Ser529) and phospho-NF-κB p65 (Ser536) and nuclear NF-κB p65 translocation in AML cells, indicating that this molecule can suppress NF-κB signalling. DNA fragmentation, nuclear condensation, cell shrinkage, phosphatidylserine externalisation, loss of transmembrane mitochondrial potential, caspase-3 activation and PARP-(Asp 214) cleavage were detected in bithionol-treated AML cells, indicating the induction of apoptosis. Furthermore, this compound increased mitochondrial superoxide levels, and bithionol-induced cell death was partially prevented by cotreatment with the selective ferroptosis inhibitor ferrostatin-1, indicating the induction of ferroptosis. In addition, bithionol synergised with venetoclax in AML cells, indicating the translational potential of bithionol to enhance the effects of venetoclax in patients with AML. Taken together, these data indicate that bithionol is a potential new anti-AML drug.

The small non-coding RNA Vaultrc5 is dispensable to mouse development.

Vault RNAs (vtRNAs) are evolutionarily conserved small non-coding RNAs transcribed by RNA polymerase lll. Vault RNAs were initially described as components of the vault particle, but have since been assigned multiple vault-independent functions including regulation of PKR activity, apoptosis, autophagy, lysosome biogenesis, and viral particle trafficking. The full-length transcript has also been described as noncanonical source of miRNAs which are processed in a DICER-dependent manner. As central molecules in vault-dependent and independent processes, vtRNAs have been attributed numerous biological roles including regulation of cell proliferation and survival, response to viral infections, drug resistance, and animal development. Yet, their impact to mammalian physiology remains largely unexplored. To study vault RNAs in vivo, we generated a mouse line with a conditional Vaultrc5 loss of function allele. Because Vaultrc5 is the sole murine vtRNA, this allele enables the characterization of the physiological requirements of this conserved class of small regulatory RNAs in mammals. Using this strain, we show that mice constitutively null for Vaultrc5 are viable and histologically normal but have a slight reduction in platelet counts pointing to a potential role for vtRNAs in hematopoiesis. This work paves the way for further in vivo characterizations of this abundant but mysterious RNA molecule. Specifically, it enables the study of the biological consequences of constitutive or lineage-specific Vaultrc5 deletion and of the physiological requirements for an intact Vaultrc5 during normal hematopoiesis or in response to cellular stresses such as oncogene expression, viral infection, or drug treatment.

Recombinant Methioninase Increases Eribulin Efficacy 16-fold in Highly Eribulin-resistant HT1080 Fibrosarcoma Cells, Demonstrating Potential to Overcome the Clinical Challenge of Drug-resistant Soft-tissue Sarcoma.

A major challenge in treating soft-tissue sarcoma is the development of drug resistance. Eribulin, an anti-tubulin agent, is used as a second-line chemotherapy for patients with unresectable or metastatic soft-tissue sarcoma. However, most patients with advanced soft-tissue sarcoma are resistant to eribulin and do not survive. Recombinant methioninase (rMETase) targets the fundamental and general hallmark of cancer, methionine addiction, termed the Hoffman Effect. The present study aimed to show how much rMETase could increase the efficacy of eribulin on eribulin-resistant fibrosarcoma cells in vitro. HT1080 human fibrosarcoma cells were exposed to step-wise increasing concentrations of eribulin from 0.15-0.4 nM to establish eribulin-resistant HT1080 (ER-HT1080). ER-HT1080 cells were cultured in vitro and divided into four groups: untreated control; eribulin treated (0.15 nM); rMETase treated (0.75 U/ml); and eribulin (0.15 nM) plus rMETase (0.75 U/ml) treated. The IC50 of eribulin on ER-HT1080 cells was 0.95 nM compared to the IC50 of 0.15 nM on HT1080 cells, a 6-fold increase. The IC50 of rMETase on ER-HT1080 and HT1080 was 0.87 U/ml and 0.75 U/ml, respectively. The combination of rMETase (0.75 U/ml) and eribulin (0.15 nM) was synergistic on ER-HT1080 cells resulting in an inhibition of 80.1% compared to eribulin alone (5.0%) or rMETase alone (47.1%) (p<0.05). rMETase thus increased the efficacy of eribulin 16-fold on eribulin-resistant fibrosarcoma cells. The present study showed that the combination of eribulin and rMETase can overcome high eribulin resistance of fibrosarcoma. The present results demonstrate that combining rMETase with first- or second-line therapy for soft-tissue sarcoma has the potential to overcome the intractable clinical problem of drug-resistant soft-tissue sarcoma.

Marine Bacteriocins: An Evolutionary Gold Mine to Payoff Antibiotic Resistance

The rapid evolution of drug resistance is one of the greatest health issues of the 21st century. There is an alarming situation to find new therapeutic strategies or candidate drugs to tackle ongoing multi-drug resistance development. The marine environment is one of the prime natural ecosystems on Earth, the majority of which is still unexplored, especially when it comes to the microbes. A wide variety of bioactive compounds have been obtained from a varied range of marine organisms; however, marine bacteria-produced bacteriocins are still undermined. Owing to the distinct environmental stresses that marine bacterial communities encounter, their bioactive compounds frequently undergo distinct adaptations that confer on them a variety of shapes and functions, setting them apart from their terrestrial counterparts. Bacterially produced ribosomally synthesized and posttranslationally modified peptides (RiPPs), known as bacteriocins, are one of the special interests to be considered as an alternative to conventional antibiotics because of their variety in structure and diverse potential biological activities. Additionally, the gut microbiome of marine creatures are a largely unexplored source of new bacteriocins with promising activities. There is a huge possibility of novel bacteriocins from marine bacterial communities that might come out as efficient candidates to fight against antibiotic resistance, especially in light of the growing pressure from antibiotic-resistant diseases and industrial desire for innovative treatments. The present review summarizes known and fully characterized marine bacteriocins, their evolutionary aspects, challenges, and the huge possibilities of unexplored novel bacteriocins from marine bacterial communities present in diverse marine ecosystems.

Oleuropein mediated autophagy begets antimalarial drug resistance

Drug resistance in Plasmodium falciparum presents a formidable challenge to the humanity. And, unavailability of an effective vaccine worsens the situation further. Autophagy is one of the mechanisms employed by parasite to evade drug pressure to survive. Autophagy induced by the P. falciparum in response to the oleuropein pressure may answer many questions related to the parasite survival as well as evolving drug tolerance. The survival/autophagy axis could be an important avenue to explore in order to address certain questions related to the evolution of drug resistance. In addition, humanized mouse model of P. falciparum infection could serve as an important preclinical tool to investigate the oleuropein-induced autophagy, potentially helping to dissect the mechanisms underlying the development of antimalarial drug resistance.

Biocontrol potential of Bacillus velezensis QF-2 isolated from rhizosphere soil of Vickifunkia tianschanica

Plant diseases caused by pathogenic fungi result in substantial losses of human, material, and financial resources annually. The common practice of chemical control often leads to the development of drug resistance in target organisms and carries adverse environmental impacts. As an alternative, researchers are exploring the potential of microbial control agents found in the rhizosphere.Previous studies have identified numerous promising microbial strains that could be utilized as effective, ecologically-friendly, and sustainable solutions to manage plant diseases. In the present investigation, a bacterial strain designated QF-2 was isolated from the rhizosphere soil of Vickifunkia tianschanica. Through dual culture experiments and molecular biological analysis, the taxonomic status of this strain was clearly established, and its antagonistic activities against seven plant pathogens were observed. Furthermore, the researchers conducted a comprehensive analysis of the QF-2 genome. Concurrently, five secondary metabolites (1–5) produced by QF-2 were studied, isolated, and identified.

A proteomics and transcriptome analysis provides insight into the molecular mechanisms of tea tree oil against Aeromonas hydrophila

Aeromonas hydrophila is a widespread fish pathogen. However, due to the extensive use of antibiotics in aquaculture, this bacterium has developed drug resistance. In recent years, tea tree oil, extracted from Melaleuca alternifolia, has gained widespread application in antibacterial research. Nevertheless, the underlying mechanism of action of tea tree oil on A. hydrophila remains unclear. In this study, the inhibitory effect of tea tree oil on A. hydrophila was analyzed, and its mechanism of action was elucidated through a combination of transcriptome and proteome analyses. In the current work, tea tree oil (0.039 mg/mL) significantly inhibited the growth of A. hydrophila and changed the permeability of the cell membrane. A total of 109 differentially expressed genes (DEGs) were identified by the combined analysis of the transcriptome and the proteome, of which 46 were upregulated and 63 were downregulated. These co-regulated DEGs were primarily enriched in metabolic pathways such as bacterial chemotaxis, pyrimidine metabolism, and the two-component system. Simultaneously, it was found that the target proteins of tea tree oil, such as secB, yajC, rpsP, rplL, and rpsT were significantly downregulated. These findings suggested that the potential of tea tree oil as an alternative to antibiotics in inhibiting the growth of A. hydrophila. It provides new insights into the molecular mechanisms underlying the antimicrobial activity of tea tree oil against A. hydrophila.

Discovery of novel dihydropyrrolidone-thiadiazole compound crosstalk between the YycG/F two-component regulatory pathway and cell membrane homeostasis to combat methicillin-resistant Staphylococcus aureus

The rapid emergence and spread of multidrug-resistant (MDR) Gram-positive pathogens present a significant challenge to global healthcare. Methicillin-resistant Staphylococcus aureus (MRSA) is a particular concern because of its high resistance to most antibiotics. Based on our previously reported chemical structure of compound 62, a series of novel derivatives were synthesized and evaluated for their antibacterial activities. We found that some of these derivatives displayed effective antibacterial activity against Gram-positive pathogens, with minimal cytotoxicity (CC50>100 μM) and hemolytic activity (HC50>200 μM). Among these derivatives, the minimum inhibitory concentration (MIC) of 62-7c against Gram-positive bacterial isolates ranged from 6.25 to 25 μM. This derivative also exhibited significant synergistic antibacterial effects with daptomycin both in vitro and in vivo, with an ability to eradicate planktonic and persister cells of MRSA. Additionally, 62-7c inhibited biofilm formation and eradicated mature biofilms of MRSA. Mechanistic studies revealed that 62-7c inhibited the YycG kinase activity and disrupted the cell membrane by binding to cardiolipin (CL), leading to cell death. Importantly, no development of drug resistance was observed even after 20 serial passages. Furthermore, 62-7c exhibited high biosafety and potent effectiveness in combating infections in both mouse pneumonia and mouse wound models infected with MRSA. Thus, our study revealed that 62-7c has the potential to serve as a novel antibacterial agent for treating MRSA infections.

Dual drug-loaded tumor-targeted polymeric nanoparticles for enhancing therapeutic response in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease where standard-of-care chemotherapeutic drugs have limited efficacy due to the development of drug resistance and poor drug delivery caused by a highly desmoplastic tumor microenvironment. Combining multiple drugs in a tumor-targeting carrier would be a favorable approach to overcome these limitations. Hence, a tumor-targeted peptide (TTP) conjugated amphiphilic tri-block copolymer was developed to make targeted polymer nanoparticles (TTP-PNPs) serving as a vehicle for carrying gemcitabine (Gem), paclitaxel (PTX), and their combination (Gem + PTX). The TTP-PNPs in the form of empty polymer (P), single drug-loaded [P(Gem) and P(PTX)], and dual drug-loaded [P(Gem + PTX)] polymer nanoformulations exhibited stable and homogenous spherical shapes with 110–160 nm size. These nanoformulations demonstrated excellent stability under in vitro physiological conditions and led to an efficient release of the drugs in the presence of reduced glutathione (GSH). The efficacy of these nanoparticles was thoroughly evaluated in vitro and in vivo, demonstrating a notable capacity to selectively target and restrict PDAC cells (PANC-1 and KPC) growth. The cellular uptake and biodistribution study showed a significantly higher tumor-targeting ability of TTP-PNPs than PNPs without TTP. Notably, P(Gem + PTX) exhibited the lowest IC50 compared to all other controls and showed heightened synergistic effects in both cell lines. Furthermore, P(Gem + PTX) showed a significantly better tumor reduction and median overall survival in mouse models than single drug-loaded TTP-PNPs or a combination of free drugs (Gem + PTX). In summary, our TTP-PNP system shows great promise as a novel platform for delivering Gem + PTX specifically to pancreatic cancer (PC), maximizing the therapeutic benefits with lower concentrations of the drugs and potentially reducing toxic side effects.

Citrus-derived flavanones as neuraminidase inhibitors: In vitro and in silico study

Neuraminidase (NA) has been well-studied as a therapeutic target for Influenza. However, resistance to the influenza virus has been observed recently. Out of special interest in the utilization of dietary antivirals from citrus, in vitro inhibition activity against NA and in silico studies including molecular docking, molecular dynamic simulation, and a predictive ADMET study, were performed on five citrus-derived flavanones. Encouragingly, citrus-derived flavanones displayed comparable or even more potent in vitro inhibitory activity than oseltamivir carboxylate against NA. Orange peel extract exhibited higher activity than hesperidin. Among the tested compounds, neohesperidin, forming strong hydrogen-bonding interactions with key arginine residues, exhibited the most effective inhibitory activity against NAs from C. perfringens, consistent with the results of molecular dynamics simulations. Although the molecular docking results were inconsistent with the in vitro activity, the binding energy was identical against the wild-type and mutant, suggesting a lower likelihood of developing drug resistance. Moreover, predictive ADMET studies showed favorable pharmacokinetic properties for the tested compounds. Overall, citrus fruit peel emerges as a promising dietary supplement for prevention and treatment of influenza. These findings elucidate the impact of flavanones on NA activity, and the analysis of their binding modes provides valuable insights into the mechanism of NA inhibition.

Kinetic Trajectories of Glucose Uptake in Single Cancer Cells Reveal a Drug-Induced Cell-State Change Within Hours of Drug Treatment.

The development of drug resistance is a nearly universal phenomenon in patients with glioblastoma multiforme (GBM) brain tumors. Upon treatment, GBM cancer cells may initially undergo a drug-induced cell-state change to a drug-tolerant, slow-cycling state. The kinetics of that process are not well understood, in part due to the heterogeneity of GBM tumors and tumor models, which can confound the interpretation of kinetic data. Here, we resolve drug-adaptation kinetics in a patient-derived in vitro GBM tumor model characterized by the epithelial growth factor receptor (EGFR) variant(v)III oncogene treated with an EGFR inhibitor. We use radiolabeled 18F-fluorodeoxyglucose (FDG) to monitor the glucose uptake trajectories of single GBM cancer cells over a 12 h period of drug treatment. Autocorrelation analysis of the single-cell glucose uptake trajectories reveals evidence of a drug-induced cell-state change from a high- to low-glycolytic phenotype after 5-7 h of drug treatment. Information theoretic analysis of a bulk transcriptome kinetic series of the GBM tumor model delineated the underlying molecular mechanisms driving the cellular state change, including a shift from a stem-like mesenchymal state to a more differentiated, slow-cycling astrocyte-like state. Our results demonstrate that complex drug-induced cancer cell-state changes of cancer cells can be captured via measurements of single cell metabolic trajectories and reveal the extremely facile nature of drug adaptation.

TEAD2 Promotes Hepatocellular Carcinoma Development and Sorafenib Resistance via TAK1 Transcriptional Activation.

Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer, yet the effectiveness of treatment for HCC patients is significantly hindered by the development of drug resistance to sorafenib. Through the application of ATAC-seq to examine drug-resistant HCC tissues, we identified substantial alterations in chromatin accessibility in sorafenib-resistant patient-derived xenograft (PDX) models. Employing multi-omics data integration analysis, we confirmed TEAD2 as a crucial transcriptional regulator in sorafenib-resistant HCC tissues. Functional assays illustrated that TEAD2 plays a role in promoting HCC progression and enhancing resistance to sorafenib. Mechanistically, we demonstrated that TEAD2 binds to the TAK1 promoter to modulate its expression. Furthermore, we established the involvement of TAK1 in mediating TEAD2-induced sorafenib resistance in HCC, a finding supported by the effectiveness of TAK1 inhibitors. Our research highlights that targeting the TEAD2-TAK1 axis can effectively mitigate drug resistance in HCC patients receiving sorafenib treatment, offering a novel approach for enhancing the treatment outcomes and prognosis of individuals with HCC. Implications: Targeting the TEAD2-TAK1 axis presents a promising therapeutic strategy to overcome sorafenib resistance in HCC, potentially improving treatment outcomes and prognosis for patients.

GCGACNN: A Graph Neural Network and Random Forest for Predicting Microbe-Drug Associations.

The interaction between microbes and drugs encompasses the sourcing of pharmaceutical compounds, microbial drug degradation, the development of drug resistance genes, and the impact of microbial communities on host drug metabolism and immune modulation. These interactions significantly impact drug efficacy and the evolution of drug resistance. In this study, we propose a novel predictive model, termed GCGACNN. We first collected microbe, disease, and drug association data from multiple databases and the relevant literature to construct three association matrices and generate similarity feature matrices using Gaussian similarity functions. These association and similarity feature matrices were then input into a multi-layer Graph Neural Network for feature extraction, followed by a two-dimensional Convolutional Neural Network for feature fusion, ultimately establishing an effective predictive framework. Experimental results demonstrate that GCGACNN outperforms existing methods in predictive performance.