Chemotherapy-resistant Cancer Research Articles

Shared chemoresistance genes in ESCC and cervical Cancer: Insights from pharmacogenomics and Mendelian randomization.

Neoadjuvant chemotherapy, particularly the use of platinum-based compounds and taxanes, is pivotal in the treatment of epithelial-derived tumors, such as cervical cancer and esophageal squamous cell carcinoma (ESCC); however, resistance remains a significant challenge. Utilizing Mendelian randomization (MR) with pharmacogenomics offers a novel approach to understanding the genetic underpinnings of drug responses, thereby aiding in personalized treatment. Single-cell RNA sequencing (scRNA-seq) analysis revealed a shared cellular subpopulation of CD8+T effector memory (CD8+TEM) cells that are pivotal in mediating chemotherapy resistance in ESCC and cervical cancer. A two-sample approach was employed for MR using data from genome-wide association studies, focusing on single nucleotide polymorphisms (SNPs) linked to CD8+TEM cell expression. The SNPs were carefully selected, and statistical models, including the Wald ratio and inverse variance weighted methods, were used for robust causal effect estimation. These were supplemented by MR-Egger and weighted median analyses to address pleiotropy and variant heterogeneity. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) and immunohistochemistry assays were used to verify the relationship between the gene and drug sensitivity. Increased proportion of CD8+TEM cells were observed in resistant samples. MR identified IL32, SPOCK1, and TRBC2 as key genes associated with resistance to cisplatin, carboplatin, and paclitaxel, respectively. These findings were validated across various cohorts and underscored the role of CD8+TEM cells in drug responsiveness. The results of the MTT and immunohistochemistry assays confirmed the MR findings. Our study highlights the significant role of CD8+TEM cells in the chemoresistance of ESCC and cervical cancer and identified three genetic markers crucial for resistance to common chemotherapeutic agents. These findings suggest potential pathways for developing personalized treatment strategies, offering clinically relevant insights that could enhance therapeutic efficacy and help overcome drug resistance in patients with ESCC or cervical cancer.

Application of a CYP1B1-Targeted NIR Probe for Breast Cancer Diagnosis, Surgical Navigation, and CYP1B1-Associated Chemotherapy Resistance Monitoring.

Early detection and precise treatment for breast cancer are crucial, given its high global incidence rate. Hence, the development of novel imaging targets is essential for diagnosing and monitoring resistance to chemotherapy, which is pivotal for achieving precise and personalized treatment for breast cancer patients. In our previous work, we successfully developed a near-infrared (NIR) probe 1 for CYP1B1-targeted imaging. In this study, we aimed to investigate the utility of the probe as a NIR fluorescence and photoacoustic dual-mode imaging probe for the detection and surveillance of breast cancer. Western blotting of cancer cell lines has confirmed that CYP1B1 is widely expressed in breast cancer and gynecological cancer. In vitro NIR fluorescence imaging capability of the probe for tracking CYP1B1-positive tumor cells was validated by using confocal microscopy. Further studies, including in vivo fluorescence and photoacoustic dual-model imaging and ex vivo biological distribution analysis on a triple-negative breast cancer xenograft mouse model, demonstrated that the probe selectively accumulated in tumor tissue within as early as 0.5 h postinjection. The results of the surgical resection experiment revealed that the tumor could be entirely removed under the guidance of NIR imaging, thereby indicating the probe's efficacy in surgical navigation. CYP1B1 expression was found to be upregulated in adriamycin (ADR)-resistant breast cancer cells, MCF-7/ADR. Consequently, the sensitivity of CYP1B1 overexpressed cells, MCF-7/1B1, to ADR was significantly reduced, with an IC50 value of 0.586 ± 0.0934 μM, compared to the parental MCF-7 cells with an IC50 value of 0.183 ± 0.0444 μM. In vivo and ex vivo imaging assays conducted on MCF-7/ADR tumor-bearing mice demonstrated that the probe was specifically enriched in tumor sites, suggesting its potential for monitoring chemotherapy resistance in breast cancer. This study expands the scope of application for NIR probe 1, establishing its utility in breast cancer diagnosis through fluorescence-photoacoustic dual-model imaging, monitoring of chemotherapy resistance, and guidance for surgical resection. This strategy paves the way for novel approaches to precise and personalized treatment for breast cancer patients.

Role of Hypoxia-Associated Long Noncoding RNAs in Cancer Chemo-Therapy Resistance

Role of Hypoxia-Associated Long Noncoding RNAs in Cancer Chemo-Therapy Resistance

Exploring extracellular RNA as drivers of chemotherapy resistance in cancer.

Chemotherapy resistance (CR) represents one of the most important barriers to effective oncological therapy and often leads to ineffective intervention and unfavorable clinical prognosis. Emerging studies have emphasized the vital significance of extracellular RNA (exRNA) in influencing CR. This thorough assessment intends to explore the multifaceted contributions of exRNA, such as exosomal RNA, microRNAs, long non-coding RNAs, and circular RNAs, to CR in cancer. We discuss the mechanisms by which exRNA facilitates drug resistance, such as modulating gene expression, influencing the tumor microenvironment, and facilitating intercellular communication. Furthermore, we examine the potential of exRNA as prognostic factor for determining oncology treatment efficacy and their emerging role as therapeutic targets. Diagnostic and prognostic applications of exRNA biomarkers are considered, alongside current methodologies for their detection and quantification. Additionally, we review recent advances in exRNA-targeted therapies, highlighting ongoing clinical trials and therapeutic strategies aimed at overcoming chemoresistance. Despite the promise of exRNA research, several challenges remain, including technical limitations and the biological complexity of exRNA networks. This review underscores the importance of continued investigation into exRNA biology and its therapeutic potential, which in the future may provide new avenues for cancer treatment and tailored medical strategies. By elucidating the role of exRNA in CR, this article aims to provide a comprehensive resource for researchers and clinicians seeking to improve the effectiveness of carcinoma management approaches.

RSL3 induces ferroptosis by activating the NF-κB signalling pathway to enhance the chemosensitivity of triple-negative breast cancer cells to paclitaxel

Chemotherapy resistance in triple-negative breast cancer (TNBC) leads to poor therapeutic effects and a poor prognosis. Given that paclitaxel-based chemotherapy is the main treatment method for TNBC, enhancing its chemosensitivity has been a research focus. Induced ferroptosis of tumour cells has been proven to increase chemosensitivity, but its ability to sensitize TNBC cells to paclitaxel (PTX) is unknown. In our experiments, measurements of viability and proliferation validated the synergistic effect of PTX combined with RSL3 on TNBC cells. The accumulation of intracellular Fe2+ and lipid reactive oxygen species, as well as the expression of malondialdehyde, illustrated that RSL3 enhanced the chemosensitivity of TNBC to PTX by inducing ferroptosis. Through transcriptome sequencing, a series of differentially expressed genes were identified, in which the expression of cytokines, such as CXCLs, was significantly increased in the treatment group, and the effect of combination therapy on TNBC was enriched mainly in the NFκB signalling pathway. In subsequent validation experiments, the use of the NF-κB inhibitor BAY11-7082 reversed the inhibitory effects of PTX and RSL3 on TNBC cell activity. In a xenograft immunodeficient mouse model, the inhibitory effects of PTX and RSL3 on TNBC in vivo were further verified. Our research validated the synergistic effects of PTX and RSL3 both in vivo and in vitro, with RSL3 inducing ferroptosis by activating the NF-κB signalling pathway, thereby increasing the chemosensitivity of TNBC to PTX. This study provides new insights for improving the therapeutic efficacy of treatment strategies.

Doxorubicin and topotecan resistance in ovarian cancer: Gene expression and microenvironment analysis in 2D and 3D models.

This study explores the mechanisms underlying chemotherapy resistance in ovarian cancer (OC) using doxorubicin (DOX) and topotecan (TOP)-resistant cell lines derived from the drug-sensitive A2780 ovarian cancer cell line. Both two-dimensional (2D) monolayer cell cultures and three-dimensional (3D) spheroid models were employed to examine the differential drug responses in these environments. The results revealed that 3D spheroids demonstrated significantly higher resistance to DOX and TOP than 2D cultures, suggesting a closer mimicry of in vivo tumour conditions. Molecular analyses identified overexpression of essential drug resistance-related genes, including MDR1 and BCRP, and extracellular matrix (ECM) components, such as MYOT and SPP1, which were more pronounced in resistant cell lines. MDR1 and BCRP overexpression contribute to chemotherapy resistance in OC by expelling drugs like DOX and TOP. Targeting these transporters with inhibitors or gene silencing could improve drug efficacy, making them key therapeutic targets to enhance treatment outcomes for drug-resistant OC. The study further showed that EMT-associated markers, including VIM, SNAIL1, and SNAIL2, were upregulated in the 3D spheroids, reflecting a more mesenchymal phenotype. These findings suggest that factors beyond gene expression, such as spheroid architecture, cell-cell interactions, and drug penetration, contribute to the enhanced resistance observed in 3D cultures. These results highlight the importance of 3D cell culture models for a more accurate representation of tumour drug resistance mechanisms in ovarian cancer, providing valuable insights for therapeutic development.

WISP1 inhibition of YAP phosphorylation drives breast cancer growth and chemoresistance via TEAD4 activation.

Wnt1-inducible signaling pathway protein 1 (WISP1) promotes breast cancer. The Hippo signaling pathway demonstrates a potential connection with WISP1, necessitating an exploration of their interaction. This study hypothesized that WISP1 boosts breast cancer by modulating the Hippo signaling pathway. The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to analyze WISP1 expression and Hippo signaling in breast cancer patients. WISP1, yes-associated protein (YAP), and domain family member 4 (TEAD4) were overexpressed or silenced in breast cancer cells. Epithelial-mesenchymal transition (EMT), and chemoresistance of breast cancer cells were evaluated. Immunofluorescence, PCR, immunoprecipitation, and western blot were used to detect the expression of WISP1 and key Hippo signaling factors and their interactions. Enrichment analysis indicated activation of WISP1 and Hippo signaling pathway and correlated with a worse prognosis in breast cancer. WISP1 overexpression facilitated EMT and chemotherapy resistance in breast cancer. Importantly, overexpression of WISP1 promoted YAP's nuclear translocation. TEAD4 expression in YAP precipitates from nuclear of WISP1-overexpressing MCF-7 cells increased. The promoting effect of WISP1 on breast cancer was counteracted by silencing YAP or TEAD4. Moreover, in WISP1 small interfering RNA-transfected MCF-7 cells, p-YAP expression increased, while interaction between YAP and TEAD4 decreased. WISP1 silencing led to ubiquitin increase and TEAD reduction in the p-YAP precipitates. In conclusion, WISP1 promotes YAP nuclear translocation and binding with TEAD4 by inhibiting YAP phosphorylation, reducing ubiquitin recruitment, and participating in transcriptional regulation in breast cancer.

GPLD1+ cancer stem cells contribute to chemotherapy resistance and tumour relapse in intestinal cancer.

Cancer stem cells (CSCs) play a central role in cancer progression, therapy resistance, and disease recurrence. With the use of a quadruple-mutant mouse intestinal cancer organoid model and single-cell RNA-sequencing analysis, we have now identified glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1), an enzyme that catalyzes the cleavage of glycosylphosphatidylinositol (GPI) anchors of membrane proteins, as a marker of slowly cycling CSCs. Ablation of Gpld1+ cells in combination with 5-fluorouracil treatment greatly attenuated cell viability in and regrowth of the intestinal cancer organoids. In addition, we identified serine protease 8 (PRSS8) as a key substrate of GPLD1 in human colorectal cancer cells. GPLD1 cleaves the GPI anchor of PRSS8 and thereby mediates release of the protease from the plasma membrane, resulting in the activation of Wnt signalling and promotion of the epithelial-mesenchymal transition (EMT) in the cancer cells. Pharmacological inhibition of GPLD1 suppressed Wnt signalling activity and EMT in association with upregulation of the amount of functional PRSS8 at the plasma membrane. Our findings suggest that targeting of GPLD1 in colorectal cancer might contribute to a new therapeutic strategy that is based on suppression of Wnt signalling and EMT-related cancer progression driven by CSCs.

M2 macrophages secrete CCL20 to regulate iron metabolism and promote daunorubicin resistance in AML cells

Chemotherapy resistance is a significant clinical challenge in the treatment of leukemia. M2 macrophages have been identified as key contributors to the development of chemotherapy resistance in cancer, yet the precise mechanisms by which macrophages regulate this resistance remain elusive. Our study has identified CCL20 as a pivotal factor in the promotion of chemoresistance in AML cells by M2 macrophages. The chemotherapeutic agent daunorubicin induces a marked increase in ROS and lipid peroxidation levels within AML cells. This is accompanied by the inhibition of the SLC7A11/GCL/GPX4 signaling axis, elevated levels of intracellular free iron, disrupted iron metabolism, and consequent mitochondrial damage, ultimately leading to ferroptosis. Notably, CCL20 enhances the ability of AML cells to maintain iron homeostasis by upregulating SLC7A11 protein activity, mitigating mitochondrial damage, and inhibiting ferroptosis, thereby contributing to chemotherapy resistance. Furthermore, in vivo experiments demonstrated that blocking CCL20 effectively restores the sensitivity of AML cells to daunorubicin chemotherapy. Collectively, these findings underscore the complex interplay between M2 macrophages, CCL20 signaling, and chemotherapy resistance in AML, highlighting potential therapeutic avenues for intervention.

PUF60 Promotes Chemoresistance Through Drug Efflux and Reducing Apoptosis in Gastric Cancer.

Background: Chemotherapy resistance is a great challenge in the treatment of gastric cancer (GC), so it is urgent to explore the prognostic markers of chemoresistance. PUF60 (Poly (U)-binding splicing factor 60) is a nucleic acid-binding protein that has been shown to regulate transcription and link to tumorigenesis in various cancers. However, its biological role and function in chemotherapy resistance of GC is unclear. Methods: The expression and prognostic value of PUF60 in GC chemotherapy-resistant patients were analyzed by databases and K-M Plotter. The functional effect of PUF60 on chemoresistance in GC was studied by by RNA interference, CCK8 test, colony formation test and apoptosis detection. Moreover, further validation and mechanism exploration were conducted in clinical samples. Results: PUF60 was highly expressed in both GC and chemoresistant tissues, and was positively correlated with poor prognosis in GC patients treated with 5-fluorouracil (5-FU). In addition, the knockdown of PUF60 significantly reduced the proliferation of human gastric cancer cells and increased sensitivity to chemotherapy drugs, such as 5-FU and cisplatin (CDDP). Mechanistically, PUF60 enhances chemotherapy resistance in gastric cancer (GC) cells by actively excluding chemotherapy drugs via the recombinant ATP Binding Cassette Transporter A1 (ABCA1) and ATP Binding Cassette Subfamily C Member 1 (ABCC1). This process further affects the cell cycle, reduces cell apoptosis, and ultimately promotes resistance to chemotherapy in GC. Conclusion: PUF60 promotes chemoresistance in GC, resulting in poor prognosis of GC patients treated with 5-FU, and providing a new idea for overcoming the chemoresistance in GC.

ADAR1 Promotes the Progression and Temozolomide Resistance of Glioma Through p62-Mediated Selective Autophagy.

Resistance to temozolomide (TMZ) remains is an important cause of treatment failure in patients with glioblastoma multiforme (GBM). ADAR1, as a member of the ADAR family, plays an important role in cancer progression and chemotherapy resistance. However, the mechanism by which ADAR1 regulates GBM progression and TMZ resistance is still unclear. We first constructed stable transfected strains in which ADAR1 was knocked down and overexpressed to investigate the effect of ADAR1 on the first-line glioma chemotherapy drug TMZ. Subsequently, we validated that ADAR1 induces autophagy activation and used autophagy inhibitors to suppress autophagy, demonstrating that ADAR1 enhances TMZ resistance through autophagy. We further knocked down p62 (SQSTM1) based on the overexpression of ADAR1, and the results showed that ADAR1 regulates selective autophagy through the p62 regulation. Finally, we demonstrated through mutations at both edited and nonedited sites that ADAR1 regulates selective autophagy in an edited dependent way. Further analysis showed that in the presence of TMZ, elevated ADAR1 promoted TMZ induced autophagy activation. Further research revealed that ADAR1 enhances TMZ resistance through p62-mediated selective autophagy. Further, ADAR1 regulates selective autophagy in an edited dependent way. Our results indicate a relationship between ADAR1 levels and the response of glioma patients to TMZ treatment. We found that the expression of ADAR1 is upregulated in GBM and is associated with tumor grade and TMZ resistance. Elevated expression of ADAR1 predicts poor prognosis in GBM patients and promotes tumor growth invivo or invitro.

Discoidin Domain Receptor 2 Contributes to Breast Cancer Progression and Chemoresistance by Interacting with Collagen Type I.

Background: Chemoresistance is an important issue to be solved in breast cancer. It is well known that the content and morphology of collagens in tumor tissues are drastically altered following chemotherapy, and discoidin domain receptor 2 (DDR2) is a unique type of receptor tyrosine kinase (RTK). This RTK is activated by collagens, playing important roles in human malignancies. However, the contribution to the chemoresistance of DDR2 in terms of the association with collagens remains largely unclear in breast cancer. Methods: We immunolocalized DDR2 and collagen type I in 224 breast cancer tissues and subsequently conducted in vitro studies to confirm the role of DDR2 in breast cancer chemoresistance using chemosensitive and chemoresistant cell lines. Results: DDR2 immunoreactivity was positively correlated with aggressive behaviors of breast cancer and was significantly associated with an increased risk of recurrence, especially in those who received chemotherapy. Moreover, in vitro experiments demonstrated that DDR2 promoted the proliferative activity of breast cancer cells, and cell viability after epirubicin treatment was significantly maintained by DDR2 in a collagen I-dependent manner. Conclusions: These data suggested that DDR2 could be a poor prognostic factor associated with cell proliferation and chemotherapy resistance in human breast cancer.

Crosstalk Between Omental Adipose-Derived Stem Cells and Gastric Cancer Cells Regulates Cancer Stemness and Chemotherapy Resistance.

Background: Peritoneal metastasis (PM) remains a major challenge in patients with gastric cancer (GC) and occurs preferentially in adipose-rich organs, such as the omentum. Adipose-derived stem cells (ASCs) may influence cancer behavior. This study aimed to investigate whether ASCs isolated from the omentum can act as progenitors of cancer-associated fibroblasts (CAFs) and analyze their effects on the cancer stem cell (CSC) niche and the treatment resistance of GC cells. Methods: ASCs were isolated from the human omentum and their cellular characteristics were analyzed during co-culturing with GC cells. Results: ASCs express CAF markers and promote desmoplasia in cancer stroma in a mouse xenograft model. When co-cultured with GC cells, ASCs enhanced the sphere-forming efficiency of MKN45 and MKN74 cells. ASCs increased IL-6 secretion and enhanced the expression of Nanog and CD44v6 in GC cells; however, these changes were suppressed by the inhibition of IL-6. Xenograft mouse models co-inoculated with MKN45 cells and ASCs showed enhanced CD44v6 and Nanog expression and markedly reduced apoptosis induced by 5-FU treatment. Conclusion: This study improves our understanding of ASCs' role in PM treatment resistance and has demonstrated the potential for new treatment strategies targeting ASCs.

Excessive glutathione intake contributes to chemotherapy resistance in breast cancer: a propensity score matching analysis

BackgroundWe aim to explore the impact of excessive glutathione (GSH) intake on chemotherapy sensitivity in breast cancer.MethodsClinicopathological data were collected from 460 breast cancer patients who underwent adjuvant chemotherapy from January 2016 to December 2019 from Zhengzhou University People’s Hospital. The clinicopathological characteristics following GSH treatment were collected and compared with those in Non-GSH group after 1:2 propensity score matching (PSM). Intracellular GSH levels and the expression of antioxidant enzymes (NRF2, GPX4 and SOD1) were evaluated in tumor tissues in 51 patients receiving neoadjuvant chemotherapy.ResultsThe recurrence rate after adjuvant chemotherapy was significantly higher in the GSH group (n = 28, 31.8%) than that in the Non-GSH group (n = 39, 22.2%; P = 0.010). Additionally, patients in the HGSH group (high GSH intake, ≥ 16 days) exhibited an elevated recurrence rate compared to that in the LGSH group (low GSH intake, < 16 days) (n = 15 (46.8%) vs. n = 52 (22.4%); P = 0.003). Cox regression revealed that High GSH intake, Ki67 ≥ 30%, Triple negative and Lymphovascular invasion were independent risk factors of progression after adjuvant chemotherapy. Among patients receiving neoadjuvant chemotherapy, intracellular GSH levels and the expression levels of antioxidant enzymes (NRF2, GPX4 and SOD1) in the resistant patients were substantially higher (P < 0.001).ConclusionsExcessive GSH intake may contribute to chemotherapy resistance in breast cancer, and the levels of intracellular GSH and antioxidant enzymes are elevated in resistant patients after neoadjuvant chemotherapy, indicating that the standardization of GSH intake may assist in reducing chemotherapy resistance.

Identification of gastric cancer stem cells with CD44 and Lgr5 double labelling and their initial roles on gastric cancer malignancy and chemotherapy resistance

Accumulating evidences have indicated that cancer stem cells (CSCs) can initiate tumor progression and cause recurrence after therapy. However, specific markers of gastric CSCs (GCSCs) from different origins have not been comprehensively revealed. Here, we further detected whether cell populations labelled with CD44 and Lgr5, well-recognized stem markers for gastric cancer (GC), can better emphasize cancer initiation, therapeutic resistance and recurrence. Flow cytometry was utilized to sort the CD44 + Lgr5 + and CD44 + Lgr5- cells from GC cell line HGC-27 and primary GC cells. The influences of CD44 and Lgr5 GCSCs on the malignant behaviors and their potential mechanisms was investigated, respectively. In our study, we reported the identification and validation of CD44 + Lgr5 + cells that presented stronger stemness characteristics, as evidenced by increase of sphere forming ability, elevation of stem cell transcriptional activity. Additionally, CD44 + Lgr5 + double positive cells have lower apoptosis, greater chemotherapy resistance, and higher EMT capacity and LC3 density compared with CD44 + Lgr5- cells. Tumor xenograft experiments also verified the faster carcinogenesis of CD44 + Lgr5 + GCSCs. Furthermore, a series of key proteins in the Wnt, Hedgehog, Notch, and TGF-β pathways were elevated in the CD44 + Lgr5 + double positive subpopulation, except for Notch 1 and Smad 1. In conclusion, the binding of CD44 and Lgr5 can serve as a precise GCSCs marker that initiate malignant progression and chemotherapy resistance in GC by activating Wnt, Hedgehog, Notch, TGF-β pathways. Those evidences raise the needs to target both markers simultaneously as a potential approach for the GC treatment.Graphical abstract1. CD44+Lgr5+ GCSCs exhibited the activation of Hedgehog pathway, and Wnt/β-catenin pathway.2. In terms of the Notch pathway, all Notch proteins and NICD were elevated in CD44+Lgr5+ GCSCs except Notch 1 protein.3. TGF/β components including TGF-β1 and Smad 2, 3, and 4 were involved in stemness phenotypes of CD44+Lgr5+ GCSCs.

PFOS and Its Commercial Alternative, 6:2 Cl-PFESA, Induce Multidrug Resistance in Pancreatic Cancer.

Per- and polyfluoroalkyl substances (PFAS), specifically perfluorooctanesulfonate (PFOS) and its alternative, 2-[(6-chloro-1,1,2,2,3,3,4,4,5,5,6,6-dodecafluorohexyl)oxy]-1,1,2,2-tetrafluoroethanesulfonic acid (6:2 Cl-PFESA), are associated with environmental health concerns and potential cancer progression. However, their impact on multidrug resistance (MDR) in pancreatic cancer (PC) chemotherapy remains unclear. Here, we employed drug-sensitivity assays, including IC50 calculations, in vitro and in vivo models with various chemotherapeutics, and paclitaxel (PTX) as a representative agent, combined with transcriptomic/proteomic sequencing and clinical prognostic analysis, to identify MDR-related genes and validate their relevance, with the objective of establishing the correlation between PFOS/6:2 Cl-PFESA exposure and MDR in PC at molecular, cellular, and animal model levels. Our findings demonstrate that PFOS/6:2 Cl-PFESA exposure increases the drug IC50 in three different PC cell lines for various chemotherapeutic agents. Compared with PFOS, 6:2 Cl-PFESA demonstrated a more pro-MDR effect on PC cells in vitro. In vivo experiments further revealed that PFOS/6:2 Cl-PFESA exposures significantly reduced the efficacy of PTX in PC, with inhibition rates dropping from 78.3% to 23.8%/6.1%, respectively (p < 0.05). This effect was driven by the aberrant activation of the PI3K-ABCB1 pathway, with 6:2 Cl-PFESA demonstrating a stronger capacity to promote this signal pathway's expression and function compared with PFOS. These data suggest that exposure to PFAS may elevate the risk of MDR and subsequent disease progression. Although marketed as a safer alternative to PFOS, the notable impact of 6:2 Cl-PFESA on MDR highlights the necessity for a comprehensive assessment of its potential carcinogenic risks.

Research progress on the role and mechanism of IGF2BPs family in head and neck squamous carcinoma

Objective:Head and neck squamous cell carcinoma（HNSCC） is one of the common malignant tumours, and most of them are in locally advanced stages at the time of diagnosis due to the lack of early symptoms, and the prognosis of such patients is still poor. M6A modification is the most common form of RNA modification in eukaryotic organisms, with a wide range of biological functions, and the family of IGF2BPs modulates growth, metastasis, chemotherapy resistance, and other processes of cancer by binding to and stabilizing a wide range of target RNAs through recognition of the m6A locus. The aim of this paper is to review the role and related mechanisms of IGF2BPs in head and neck squamous carcinoma, and to provide new ideas for early diagnosis and precision treatment of HNSCC.

A mathematical framework for comparison of intermittent versus continuous adaptive chemotherapy dosing in cancer

Chemotherapy resistance in cancer remains a barrier to curative therapy in advanced disease. Dosing of chemotherapy is often chosen based on the maximum tolerated dosing principle; drugs that are more toxic to normal tissue are typically given in on-off cycles, whereas those with little toxicity are dosed daily. When intratumoral cell-cell competition between sensitive and resistant cells drives chemotherapy resistance development, it has been proposed that adaptive chemotherapy dosing regimens, whereby a drug is given intermittently at a fixed-dose or continuously at a variable dose based on tumor size, may lengthen progression-free survival over traditional dosing. Indeed, in mathematical models using modified Lotka-Volterra systems to study dose timing, rapid competitive release of the resistant population and tumor outgrowth is apparent when cytotoxic chemotherapy is maximally dosed. This effect is ameliorated with continuous (dose modulation) or intermittent (dose skipping) adaptive therapy in mathematical models and experimentally, however, direct comparison between these two modalities has been limited. Here, we develop a mathematical framework to formally analyze intermittent adaptive therapy in the context of bang-bang control theory. We prove that continuous adaptive therapy is superior to intermittent adaptive therapy in its robustness to uncertainty in initial conditions, time to disease progression, and cumulative toxicity. We additionally show that under certain conditions, resistant population extinction is possible under adaptive therapy or fixed-dose continuous therapy. Here, continuous fixed-dose therapy is more robust to uncertainty in initial conditions than adaptive therapy, suggesting an advantage of traditional dosing paradigms.

Navigating the Complexity of Resistance in Lung Cancer Therapy: Mechanisms, Organoid Models, and Strategies for Overcoming Treatment Failure.

Background: The persistence of chemotherapy-resistant and dormant cancer cells remains a critical challenge in the treatment of lung cancer. Objectives: This review focuses on non-small cell lung cancer and small cell lung cancer, examining the complex mechanisms that drive treatment resistance. Methods: This review analyzed current studies on chemotherapy resistance in NSCLC and SCLC, focusing on tumor microenvironment, genetic mutations, cancer cell heterogeneity, and emerging therapies. Results: Conventional chemotherapy and targeted therapies, such as tyrosine kinase inhibitors, often fail due to factors including the tumor microenvironment, genetic mutations, and cancer cell heterogeneity. Dormant cancer cells, which can remain undetected in a quiescent state for extended periods, pose a significant risk of recurrence upon reactivation. These cells, along with intrinsic resistance mechanisms, greatly complicate treatment efforts. Understanding these pathways is crucial for the development of more effective therapies. Emerging strategies, including combination therapies that target multiple pathways, are under investigation to improve treatment outcomes. Innovative approaches, such as antibody-drug conjugates and targeted protein degradation, offer promising solutions by directly delivering cytotoxic agents to cancer cells or degrading proteins that are essential for cancer survival. The lung cancer organoid model shows substantial promise to advance both research and clinical applications in this field, enhancing the ability to study resistance mechanisms and develop personalized treatments. The integration of current research underscores the need for continuous innovation in treatment modalities. Conclusions: Personalized strategies that combine novel therapies with an in-depth understanding of tumor biology are essential to overcome the challenges posed by treatment-resistant and dormant cancer cells in lung cancer. A multifaceted approach has the potential to significantly improve patient outcomes.

CRISPR/Cas9 system: a novel approach to overcome chemotherapy and radiotherapy resistance in cancer.

Cancer presents a global health challenge with rising incidence and mortality. Despite treatment advances in cancer therapy, radiotherapy and chemotherapy remained the most common treatments for all types of cancers. However, resistance phenotype in cancer cells leads to unsatisfactory results in the efficiency of therapeutic strategies. Therefore, researchers strive to propose effective solutions to overcome treatment failure, which requires a deep knowledge of treatment-resistant mechanisms. The progression and occurrence of tumors can be attributed to gene mutation. Over the past decade, the emergence of clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9) genome editing has revolutionized cancer research. This versatile technology enables cancer modeling, manipulation of specific DNA sequences, and genome-wide screening. CRISPR/Cas9 is an effective tool for identifying radio- and chemoresistance genes and offering potential adjunctive treatments to overcome tumor recurrence after chemo- and radiotherapy. This article aims to explain the potential of the CRISPR/Cas9 system in improving the effectiveness of chemo- and radiotherapy and ultimately overcoming treatment failure.