Mechanisms Of Resistance Research Articles

Antibody-Drug Conjugates as Novel Therapeutic Agents for Non-Small Cell Lung Carcinoma with or without Alterations in Oncogenic Drivers.

Antibody-drug conjugates (ADCs) are an emerging class of therapeutics for lung cancer, and several are currently in development for this malignancy. The structure of these molecules is based on an antibody that targets a protein on the lung cancer cell surface and a cytotoxic payload attached by a linker. Many protein targets, including TROP2, c-MET, CEACAM5, HER2, and HER3 have been identified. In metastatic non-small cell lung carcinoma (NSCLC) without alterations in oncogenic drivers, platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) targeting the programmed death-1/programmed death-ligand 1 (PD1/PDL1) interaction are the standard first-line treatments. In patients with EGFR-mutated or ALK-rearranged NSCLC, tyrosine kinase inhibitors (TKIs) are recommended. However, although the prognosis of patients with metastatic NSCLC differs between such with and without alterations in oncogenic drivers, most patients eventually experience disease progression. A novel therapeutic class is needed in routine practice to overcome the mechanisms of resistance to ICIs and EGFR/ALK TKIs. Several ADCs have already been approved for other cancers, such as breast cancer and urothelial carcinoma. This review summarizes the knowledge about the efficacy and tolerance profiles of ADCs targeting TROP2, HER2, HER3, CEACAM5 and c-MET in metastatic NSCLC with and without alterations in oncogenic drivers.

Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation.

Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/β inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.

The effect of the COVID-19 pandemic on the incidence and resistance in Gram-negative bacilli and antimicrobial consumption in the Intensive Care Units of a referral hospital in Buenos Aires.

A retrospective time series study from Intensive Care Units, to address changes in antibiotic consumption (DDD/1000 patients/day), the incidence of Gram-negative bacilli (GNB) and the mechanism of resistance. Antibiotics were categorised in group 1 (agents against multi-drug resistant MDR GNB) and group 2 (agents against non-MDR infections). Bacteriological samples included respiratory samples and blood cultures. Periods were divided into pre-pandemic (July 2019 to March 2020) and pandemic (April 2020 to March 2022). Correlation coefficients (r) were analyzed and Mann-Whitney test was performed to compare both periods. During the study period, GNB incidence, group 1 antibiotics consumption and resistance mechanisms increased, whereas group 2 antibiotics decreased. A significant positive correlation was observed between the consumption of antibiotics in group 1 and the incidence of GNB (r=0,63; p<0.001) and resistance (r=0,52; p=0.002). Significant differences were found between pre-pandemic and pandemic periods regarding the medians of group 1 consumption (520 [408-570] vs 753 [495-851] DDD/1000 patients/day; p=0.029); incidence of GNB (12 [10-13] vs 43 [25-52.5] cases/month; p<0.001) and resistance mechanisms (5 [4-8] vs 17 [10-25] cases/month; p<0.001), ESBL (2 [1-2] vs 6 [3-8] cases/month; p<0.001) and MBL (0 [0-0] vs 6 [1.75-8.5] cases/month; p <0.001). During the pandemic, the rise of GNB incidence and in the amount of resistance mechanisms significantly correlated with the increase in consumption of agents against MDR strains.

Targeting PI3K/AKT/mTOR Signaling to Overcome Drug Resistance in Cancer.

This review comprehensively explores the challenge of drug resistance in cancer by focusing on the pivotal PI3K/AKT/mTOR pathway, elucidating its role in oncogenesis and resistance mechanisms across various cancer types. It meticulously examines the diverse mechanisms underlying resistance, including genetic mutations, feedback loops, and microenvironmental factors, while also discussing the associated resistance patterns. Evaluating current therapeutic strategies targeting this pathway, the article highlights the hurdles encountered in drug development and clinical trials. Innovative approaches to overcome resistance, such as combination therapies and precision medicine, are critically analyzed, alongside discussions on emerging therapies like immunotherapy and molecularly targeted agents. Overall, this comprehensive review not only sheds light on the complexities of resistance in cancer but also provides a roadmap for advancing cancer treatment.

Recent advances in the effect of adipose tissue inflammation on insulin resistance.

Obesity is one of the major risk factors for diabetes. Excessive accumulation of fat leads to inflammation of adipose tissue, which can increase the risk of developing diabetes.. Obesity-related chronic inflammation can result in anomalies in glucose-lipid metabolism and insulin resistance, and it is a major cause of β-cell dysfunction in diabetes mellitus. Thus, a long-term tissue inflammatory response is crucial for metabolic diseases, particularly type 2 diabetes. Chronic inflammation associated with obesity increases oxidative stress, secretes inflammatory factors, modifies endocrine variables, and interferes with insulin signalling pathways, all of which contribute to insulin resistance and glucose tolerance. Insulin resistance and diabetes are ultimately caused by chronic inflammation in the stomach, pancreas, liver, muscle, and fat tissues. In this article, we systematically summarize the latest research progress on the mechanisms of adipose tissue inflammation and insulin resistance, as well as the mechanisms of cross-talk between adipose tissue inflammation and insulin resistance, with a view to providing some meaningful therapeutic strategies for the treatment of insulin resistance by controlling adipose tissue inflammation.

Function of MYB8 in larch under PEG simulated drought stress.

Larch, a prominent afforestation, and timber species in northeastern China, faces growth limitations due to drought. To further investigate the mechanism of larch's drought resistance, we conducted full-length sequencing on embryonic callus subjected to PEG-simulated drought stress. The sequencing results revealed that the differentially expressed genes (DEGs) primarily played roles in cellular activities and cell components, with molecular functions such as binding, catalytic activity, and transport activity. Furthermore, the DEGs showed significant enrichment in pathways related to protein processing, starch and sucrose metabolism, benzose-glucuronic acid interconversion, phenylpropyl biology, flavonoid biosynthesis, as well as nitrogen metabolism and alanine, aspartic acid, and glutamic acid metabolism. Consequently, the transcription factor T_transcript_77027, which is involved in multiple pathways, was selected as a candidate gene for subsequent drought stress resistance tests. Under PEG-simulated drought stress, the LoMYB8 gene was induced and showed significantly upregulated expression compared to the control. Physiological indices demonstrated an improved drought resistance in the transgenic plants. After 48h of PEG stress, the transcriptome sequencing results of the transiently transformed LoMYB8 plants and control plants exhibited that genes were significantly enriched in biological process, cellular component and molecular function. Function analyses indicated for the enrichment of multiple KEGG pathways, including energy synthesis, metabolic pathways, antioxidant pathways, and other relevant processes. The pathways annotated by the differential metabolites mainly encompassed signal transduction, carbohydrate metabolism, amino acid metabolism, and flavonoid metabolism.

Evaluation of drug resistance for EGFR-TKIs in Lung Cancer via Multicellular lung-on-a-chip.

Drug resistance to irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a primary factor affecting their therapeutic efficacy in human non-small cell lung cancer (NSCLC). NSCLC cells can undergo epithelial-mesenchymal transition (EMT) induced by many factors in the tumour microenvironment (TME), which plays a crucial role in tumour drug resistance. In this study, a multicellular lung-on-a-chip that can realise the cell co-culture of the human non-small cell lung cancer cell line HCC827, human foetal lung fibroblasts (HFL-1), and human umbilical vein endothelial cells (HUVECs) is prepared. The TME was simulated on the chip combined with perfusion and other factors, and the drug evaluation of osimertinib was performed to explore the drug resistance mechanism of EGFR-TKIs. In the early stages, a two-dimensional static cell co-culture was achieved by microchip, and the results showed that HFL-1 cells could be transformed into cancer-associated fibroblasts (CAFs), and HCC827 cells could undergo EMT, both of which were mediated by Interleukin-6 (IL-6). Vimentin (VIM) and Alpha Skeletal Muscle Actin (a-SMA) expression of HFL-1 was upregulated, whereas E-cadherin (E-cad) expression of HCC827 was down-regulated. Further, N-cadherin (N-cad) expression of HCC827 was upregulated. In both the static cell co-culture and multicellular lung-on-a-chip, HCC827 cells with CAFs co-culture or IL-6 treatment developed resistance to osimertinib. Further use of the IL-6 antibody inhibitor tocilizumab could reverse EGFR-TKI resistance to a certain extent. Combination therapy with tocilizumab and EGFR-TKIs may provide a novel therapeutic strategy for overcoming EGFR-TKI resistance caused by EMT in NSCLC. Furthermore, the lung-on-a-chip can simulate complex TME and can be used for evaluating tumour resistance and exploring mechanisms, with the potential to become an important tool for personalised diagnosis, treatment, and biomedical research.

Tyrosine Kinase Inhibitors in Cancers: treatment optimization - Part I.

A multitude of TKI has been developed and approved targeting various oncogenetic alterations. While these have provided improvements in efficacy compared with conventional chemotherapies, resistance to targeted therapies occurs. Mutations in the kinase domain result in the inability of TKI to inactivate the protein kinase. Also, gene amplification, increased protein expression and downstream activation or bypassing of signalling pathways are commonly reported mechanisms of resistance. Improved understanding of mechanisms involved in TKI resistance has resulted in the development of new generations of targeted agents. In a race against time, the search for new, more potent and efficient drugs, and/or combinations of drugs, remains necessary as new resistance mechanisms to the latest generation of TKI emerge. This review examines the various generations of TKI approved to date and their common mechanisms of resistance, focusing on TKI targeting BCR-ABL, epidermal growth factor receptor, anaplastic lymphoma kinase and BRAF/MEK tyrosine kinases.

Proteomic assay for rapid characterisation of Staphylococcus aureus antimicrobial resistance mechanisms directly from blood cultures.

Staphylococcus aureus is one of the most common pathogens causing bloodstream infection. A rapid characterisation of resistance to methicillin and, occasionally, to aminoglycosides for particular indications, is therefore crucial to quickly adapt the treatment and improve the clinical outcomes of septic patients. Among analytical technologies, targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as a promising tool to detect resistance mechanisms in clinical samples. A rapid proteomic method was developed to detect and quantify the most clinically relevant antimicrobial resistance effectors in S. aureus in the context of sepsis: PBP2a, PBP2c, APH(3')-III, ANT(4')-I, and AAC(6')-APH(2''), directly from positive blood cultures and in less than 70min including a 30-min cefoxitin-induction step. The method was tested on spiked blood culture bottles inoculated with 124 S.aureus, accounting for the known genomic diversity of SCCmec types and the genetic background of the strains. This method provided 99% agreement for PBP2a (n = 98/99 strains) detection. Agreement was 100% for PBP2c (n = 5/5), APH(3')-III (n = 16/16), and ANT(4')-I (n = 20/20), and 94% for AAC(6')-APH(2'') (n = 16/17). Across the entire strain collection, 100% negative agreement was reported for each of the 5 resistance proteins. Additionally, relative quantification of ANT(4')-I expression allowed to discriminate kanamycin-susceptible and -resistant strains, in all strains harbouring the ant(4')-Ia gene. The LC-MS/MS method presented herein demonstrates its ability to provide a reliable determination of S. aureus resistance mechanisms, directly from positive blood cultures and in a short turnaround time, as required in clinical laboratories.

Exploring the diversity of cancer-associated fibroblasts: insights into mechanisms of drug resistance

Exploring the diversity of cancer-associated fibroblasts: insights into mechanisms of drug resistance

Sustainable engineering of human hair fiber-composite in engineering application

The hybrid composite material, resulting from the fusion of human hair and Kevlar 29 synthetic fiber in a 10:1 ratio, reinforced with epoxy resin using the hand layup technique, underwent meticulous mechanical and thermal testing. The investigation encompassed tensile, flexural, and impact property evaluations, elucidating a notable enhancement in mechanical strength with a diminishing synthetic fiber content. Concomitantly, the composite exhibited commendable heat resistance in heat deflection tests, making it potentially suitable for applications in elevated temperature environments. Water absorption properties were scrutinized, revealing a correlation between reduced synthetic fiber content and diminished water absorption, implying heightened durability in diverse conditions. Microstructure analysis through SEM provided intricate insights into the internal composition. In summation, the composite, featuring a higher proportion of natural fibers and a lower proportion of synthetics, demonstrated superior mechanical attributes, optimal heat resistance, and reduced water absorption, showcasing its applicability in automotive and engineering domains, particularly in the fabrication of vehicle panels and components. The aim of this research represents a significant advancement in composite materials, offering a cost-effective solution that balances mechanical strength and thermal resistance. It suggests the potential for high-performance materials by combining natural and synthetic fibers, promising versatility across various applications.

Dose Optimization in Oncology Drug Development: An International Consortium for Innovation and Quality in Pharmaceutical Development White Paper.

The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current practices, provide recommendations for improvement, develop a clinical toolkit, and engage Health Authorities. Historically, dose selection for cytotoxic chemotherapeutics has focused on the maximum tolerated dose, a paradigm that is less relevant for targeted therapies and new treatment modalities. A survey conducted by this group gathered insights from member companies regarding industry practices in oncology dose optimization. Given oncology drug development is a complex effort with multidimensional optimization and high failure rates due to lack of clinically relevant efficacy, this Working Group advocates for a case-by-case approach to inform the timing, specific quantitative targets, and strategies for dose optimization, depending on factors such as disease characteristics, patient population, mechanism of action, including associated resistance mechanisms, and therapeutic index. This white paper highlights the evolving nature of oncology dose optimization, the impact of Project Optimus, and the need for a tailored and evidence-based approach to optimize oncology drug dosing regimens effectively.

Photodynamic Inactivation in agriculture: combating fungal phytopathogens resistant to conventional treatment.

Botrytiscinerea is a severe threat in agriculture, as it can infect over 200 different crop species with gray mold affecting food yields and quality. The conventional treatment using fungicides lead to emerging resistance over the past decades. Here, we introduce Photodynamic Inactivation (PDI) as a strategy to combat B.cinerea infections, independent of fungicide resistance. PDI uses photoactive compounds, which upon illumination create reactive oxygen species toxic forkilling target organisms. This study focuses on different formulations of sodium-magnesium-chlorophyllin (Chl, food additive E140) as photoactive compound in combination with EDTA disodium salt dihydrate (Na2EDTA) as cell-wall permeabilizer and a surfactant. In an in vitro experiment, three different photosensitizers (PS)with varying Chl and Na2EDTA concentrations were tested against five B.cinerea strains with different resistance mechanisms. We showed that all B.cinerea mycelial spheres of all tested strains were eradicated with concentrations as low as 224µM Chl and 3.076mM Na2EDTA (LED illumination with main wavelength of 395nm, radiant exposure 106Jcm-2). To further test PDI as a Botrytis treatment strategy in agriculture a greenhouse trial was performed on B.cinerea infected bell pepper plants (CapsicumannumL). Two different rates (560 or 1120gHa-1) of PS formulation (0.204M Chl and 1.279M Na2EDTA) and a combination of PS formulation with 0.05% of the surfactant BRIJL4 (560gHa-1) were applied weekly for 4 weeks by spray application. Foliar lesions, percentage of leaves affected, percentage of leaf area diseased and AUDPC were significantly reduced, while percentage of marketable plants were increased by all treatments compared to a watertreated control, however, did not statistically differ from each other. No phytotoxicity was observed in any treatment. These results add to the proposition of employing PDI with the naturally sourced PS Chl in agricultural settings aimed at controlling B.cinerea disease. This approach seems to be effective regardless of the evolving resistance mechanisms observed in response to conventional antifungal treatments.

Magnaporthe oryzae infection triggers rice resistance to brown planthopper through the influence of jasmonic acid on the flavonoid biosynthesis pathway.

In agroecosystems, plants are constantly exposed to attack from diverse herbivorous insects and microbes, and infestation with one species may change the plant defense response to other species. In our investigation of the relationships among rice plants, the brown planthopper Nilaparvata lugens (Stål) and the rice blast fungus Magnaporthe oryzae, we observed a significant increase in the resistance of rice treated with rice blast to N.lugens, as evidenced by improved plant survival rates in a small population resistance study. Subsequent transcriptome data analysis revealed that the rice blast fungus can induce the expression of genes in the jasmonic acid (JA) and flavonoid pathways. Similar to the flavonoid pathway, the JA pathway also contains 2 types of genes that exhibit similar and opposite trends in response to N.lugens and rice blast. Among these genes, the osjaz1 mutant and the osmyc2 mutant were phenotypically confirmed to positively and negatively regulate rice resistance to N.lugens and rice blast, respectively. Subsequent mass spectrometry and quantification experiments showed that the exogenous application of methyl jasmonate (MeJA) can induce the accumulation of eriodictyol, naringenin and quercetin, as well as the expression of OsF3H, Os4CL5 and OsCHI in the flavonoid pathway. This suggests a close connection between the JA pathway and the flavonoid pathway. However, OsF3'H, which negatively regulates rice resistance to N.lugens and rice blast, did not show increased expression. Phenotypic and molecular experiments confirmed that OsMYC2 can bind to and inhibit the expression of OsF3'H, thus revealing the mechanism of rice resistance to N.lugens after treatment with rice blast. These findings will deepen our understanding of the interactions among rice, N.lugens and rice blast.

Physiological and transcriptomic analyses reveal the cadmium tolerance mechanism of Miscanthus lutarioriparia.

Miscanthus lutarioriparia is a promising energy crop that is used for abandoned mine soil phytoremediation because of its high biomass yield and strong tolerance to heavy metals. However, the biological mechanism of heavy metal resistance is limited, especially for applications in the soil restoration of mining areas. Here, through the investigation of soil cadmium(Cd) in different mining areas and soil potted under Cd stress, the adsorption capacity of Miscanthus lutarioriparia was analyzed. The physiological and transcriptional effects of Cd stress on M. lutarioriparia leaves and roots under hydroponic conditions were analyzed. The results showed that M. lutarioriparia could reduce the Cd content in mining soil by 29.82%. Moreover, different Cd varieties have different Cd adsorption capacities in soils with higher Cd concentration. The highest cadmium concentrations in the aboveground and belowground parts of the plants were 185.65 mg/kg and 186.8 mg/kg, respectively. The total chlorophyll content, superoxide dismutase and catalase activities all showed a trend of increasing first and then decreasing. In total, 24,372 differentially expressed genes were obtained, including 7735 unique to leaves, 7725 unique to roots, and 8912 unique to leaves and roots, which showed differences in gene expression between leaves and roots. These genes were predominantly involved in plant hormone signal transduction, glutathione metabolism, flavonoid biosynthesis, ABC transporters, photosynthesis and the metal ion transport pathway. In addition, the number of upregulated genes was greater than the number of downregulated genes at different stress intervals, which indicated that M. lutarioriparia adapted to Cd stress mainly through positive regulation. These results lay a solid foundation for breeding excellent Cd resistant M. lutarioriparia and other plants. The results also have an important theoretical significance for further understanding the detoxification mechanism of Cd stress and the remediation of heavy metal pollution in mining soil.

Combating antimicrobial resistance in malaria, HIV and tuberculosis.

Antimicrobial resistance poses a significant threat to the sustainability of effective treatments against the three most prevalent infectious diseases: malaria, human immunodeficiency virus (HIV) infection and tuberculosis. Therefore, there is an urgent need to develop novel drugs and treatment protocols capable of reducing the emergence of resistance and combating it when it does occur. In this Review, we present an overview of the status and underlying molecular mechanisms of drug resistance in these three diseases. We also discuss current strategies to address resistance during the research and development of next-generation therapies. These strategies vary depending on the infectious agent and the array of resistance mechanisms involved. Furthermore, we explore the potential for cross-fertilization of knowledge and technology among these diseases to create innovative approaches for minimizing drug resistance and advancing the discovery and development of new anti-infective treatments. In conclusion, we advocate for the implementation of well-defined strategies to effectively mitigate and manage resistance in all interventions against infectious diseases.

Performance of Earth Plasters with Graphene-Based Additive

A central debate is the improvement in the mechanical and water resistance of sustainable earthen architecture without additives or stabilizers. This innovative work aims to test the effects of a graphene-based additive, optimized for the improvement in concrete properties, on the strength and water resistance of raw-earth plasters without any stabilizer other than sand. Given the heterogeneous nature of raw earth, three different soils were tested by adding three increasing graphene-based additive contents (0.01, 0.05 and 0.1 wt% of the earth–sand proportion). The link between soil intrinsic properties, i.e., geotechnical and mineralogical properties, and their interaction with the additive were investigated through geotechnical characterization, as well as mineralogical characterization, by XRD and ATR-FTIR analyses. The experimental tests carried out focused on the adhesion properties of the twelve different plasters on standard hollow bricks and on their interaction with water through capillary rise tests and erosion resistance tests. Conclusion from the experimental tests suggests that the graphene-based additive in earth plasters, by increasing the cohesion of the mixture, improves their adhesion performance.

Circulating Tumor DNA as a Complementary Prognostic Biomarker during CAR-T Therapy in B-Cell Non-Hodgkin Lymphomas

The emergence of CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment paradigm for R/R B-cell NHLs. However, challenges persist in accurately evaluating treatment response and detecting early relapse, necessitating the exploration of novel biomarkers. Circulating tumor DNA (ctDNA) via liquid biopsy is a non-invasive tool for monitoring therapy efficacy and predicting treatment outcomes in B-NHL following CAR-T therapy. By overcoming the limitations of conventional imaging modalities, ctDNA assessments offer valuable insights into response dynamics, molecular mechanisms of resistance, and early detection of molecular relapse. Integration of ctDNA monitoring into clinical practice holds promise for personalized therapeutic strategies, guiding the development of novel targeted therapies, and enhancing patient outcomes. However, standardization of assay methodologies and consensus on clinical response metrics are imperative to unlock the full potential of ctDNA in the management of B-NHL. Prospective validation of ctDNA in clinical trials is necessary to establish its role as a complementary decision aid.

Genome-wide identification analysis in wild-type Solanum pinnatisectum reveals some genes defending against Phytophthora infestans

Solanum pinnatisectum exhibits strong resistance to late blight caused by Phytophthora infestans but only an incomplete genome assembly based on short Illumina reads has been published. In this study, we generated the first chromosome-level draft genome for the wild-type potato species S. pinnatisectum in China using Oxford Nanopore technology sequencing and Hi-C technology. The high-quality assembled genome size is 664 Mb with a scaffold N50 value of 49.17 Mb, of which 65.87% was occupied by repetitive sequences, and predominant long terminal repeats (42.51% of the entire genome). The genome of S. pinnatisectum was predicted to contain 34,245 genes, of which 99.34% were functionally annotated. Moreover, 303 NBS-coding disease resistance (R) genes were predicted in the S. pinnatisectum genome to investigate the potential mechanisms of resistance to late blight disease. The high-quality chromosome-level reference genome of S. pinnatisectum is expected to provide potential valuable resources for intensively and effectively investigating molecular breeding and genetic research in the future.

Metabolic Resistance and Not Voltage-Gated Sodium Channel Gene Mutation Is Associated with Pyrethroid Resistance of Aedes albopictus (Skuse, 1894) from Cambodia

(1) Background: In Cambodia, Aedes albopictus is an important vector of the dengue virus. Vector control using insecticides is a major strategy implemented in managing mosquito-borne diseases. Resistance, however, threatens to undermine the use of insecticides. In this study, we present the levels of insecticide resistance of Ae. albopictus in Cambodia and the mechanisms involved. (2) Methods: Two Ae. albopictus populations were collected from the capital, Phnom Penh city, and from rural Pailin province. Adults were tested with diagnostic doses of malathion (0.8%), deltamethrin (0.03%), permethrin (0.25%), and DDT (4%) using WHO tube assays. Synergist assays using piperonyl butoxide (PBO) were implemented before the pyrethroid assays to detect the potential involvement of metabolic resistance mechanisms. Adult female mosquitoes collected from Phnom Penh and Pailin were tested for voltage-gated sodium channel (VGSC) kdr (knockdown resistance) mutations commonly found in Aedes sp.-resistant populations throughout Asia (S989P, V1016G, and F1534C), as well as for other mutations (V410L, L982W, A1007G, I1011M, T1520I, and D1763Y). (3) Results: The two populations showed resistance against all the insecticides tested (&lt;90% mortality). The use of PBO (an inhibitor of P450s) strongly restored the efficacy of deltamethrin and permethrin against the two resistant populations. Sequences of regions of the vgsc gene showed a lack of kdr mutations known to be associated with pyrethroid resistance. However, four novel non-synonymous mutations (L412P/S, C983S, Q1554STOP, and R1718L) and twenty-nine synonymous mutations were detected. It remains to be determined whether these mutations contribute to pyrethroid resistance. (4) Conclusions: Pyrethroid resistance is occurring in two Ae. albopictus populations originating from urban and rural areas of Cambodia. The resistance is likely due to metabolic resistance specifically involving P450s monooxygenases. The levels of resistance against different insecticide classes are a cause for concern in Cambodia. Alternative tools and insecticides for controlling dengue vectors should be used to minimize disease prevalence in the country.