Resistant Cancer Research Articles

In silico and in vitro assessment of TP53, ATM, RAD51, and BAX genes in gastric cancer and their contribution to radiotherapy resistance

BackgroundGastric cancer remains a leading cause of cancer-related morbidity and mortality worldwide. The genetic factors contributing to gastric cancer progression and resistance to therapies, particularly radiotherapy, are not fully understood. TP53, ATM, RAD51, and BAX are genes involved in DNA repair, apoptosis, and response to stress. The aim of this study was to investigate the expression patterns of these genes in gastric cancer, their potential role in radiotherapy resistance, and their diagnostic value.MethodologyGene expression levels of TP53, ATM, RAD51, and BAX were assessed using RT-qPCR across 9 gastric cancer cell lines and 6 normal control cell lines. Additionally, protein expression was confirmed via IHC and TCGA dataset analysis. Methylation levels of these genes were evaluated in gastric cancer tissues using the GSCA database. Mutational analysis was conducted using cBioPortal, and survival analysis was performed using Kaplan-Meier and meta-analysis. The radiotherapy resistance study was carried out by knocking down TP53, RAD51, and BAX in AGS and MKN-45 gastric cancer cell lines, followed by expression analysis, colony formation, and wound healing assays.ResultsThe expression of TP53, RAD51, and BAX was significantly upregulated, while ATM was downregulated in gastric cancer cell lines compared to normal controls. All four genes demonstrated good discriminatory power (AUC = 1) in distinguishing gastric cancer from normal samples. Methylation analysis revealed significant hypomethylation of TP53, RAD51, and BAX, and hypermethylation of ATM in gastric cancer tissues. Mutational analysis showed that TP53 was altered in 88% of gastric cancer samples, while ATM, RAD51, and BAX exhibited lower mutation rates. Survival analysis suggested that elevated expression of TP53, RAD51, and BAX may be linked to poorer survival outcomes, while reduced ATM expression appeared to associate with decreased overall survival. However, these associations require further validation through additional studies. Knockdown of TP53, RAD51, and BAX in AGS and MKN-45 cells resulted in significantly reduced cell proliferation and slower wound healing, highlighting their role in radiotherapy resistance.ConclusionThe TP53, RAD51, and BAX genes are significantly involved in gastric cancer progression and resistance to radiotherapy. Their expression and mutation status provide valuable diagnostic and prognostic information.

Organometallic Half-Sandwich Complexes of 1,10-Phenanthroline Derivatives with Improved Solubility, Albumin-Binding, and Nanoformulation Potential Targeting Drug Resistance in Cancer.

The development of Rh(III)(η5-C5Me5) and Ru(II)(η6-p-cymene) complexes of 4,7-dichloro-1,10-phenanthroline (DCP) and bathophenanthroline (BP) aims to increase aqueous solubility and potential bioavailability of the lipophilic ligands while also enabling selective activity against multidrug-resistant (MDR) cancer cells. Complexes [M(η6-arene/η5-arenyl)(DCP/BP)Cl]Cl were prepared and characterized by means of nuclear magnetic resonance, infrared, electrospray ionization mass spectrometry, and single crystal X-ray diffraction for [Rh(III)(η5-C5Me5)(DCP)Cl]PF6 and [Ru(II)(η6-p-cymene)(BP)Cl]PF6. The complexes are highly stable in a wide pH range with increased hydrophilicity, and the Rh complexes showed fast and significant binding to human serum albumin (HSA). Cytotoxicity tests were conducted in various breast cancer cells and in cocultured cell lines of the uterine sarcoma parental MES-SA and its MDR counterparts. Both the ligands and their organorhodium complexes displayed a higher cytotoxicity against the MDR MES-SA/Dx5 cells than against the parental cells. As the complex [Rh(III)(η5-C5Me5)(BP)Cl]Cl showed the most promising results (IC50 = 0.23 μM (MES-SA/Dx5) with selectivity ratio 6.7), it was selected for nanoformulation using HSA and also combined with d-α-tocopheryl polyethylene glycol 1000 succinate and poly(lactic-co-glycolic acid). Both composites showed a good encapsulation efficiency and colloidal stability. Based on the in vitro cytotoxicity assays, the use of HSA as a carrier is a promising strategy to enhance the pharmacological properties of the MDR-selective Rh(III)(η5-C5Me5) complexes of 1,10-phenanthroline derivatives.

Lestaurtinib’s antineoplastic activity converges on JAK/STAT signaling to inhibit treatment naïve and therapy resistant forms ovarian cancer

Ovarian cancer is the deadliest gynecological malignancy, owing to its late-stage diagnosis and high rates of recurrence and resistance following standard-of-care treatment, highlighting the need for novel treatment approaches. Through an unbiased drug screen, we identified the kinase inhibitor, lestaurtinib, as a potent antineoplastic agent for chemotherapy- and PARP-inhibitor (PARPi)-sensitive and -resistant ovarian cancer cells and patient derived xenografts (PDXs). RNA-sequencing revealed that lestaurtinib potently suppressed JAK/STAT signaling and lestaurtinib efficacy was shown to be directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive JAK/STAT pathway activation and genetic loss of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib also displayed synergy when combined with cisplatin and olaparib, including in a model of PARPi resistance. In contrast, the most well-known JAK/STAT inhibitor, ruxolitinib, lacked antineoplastic activity against all ovarian cancer cell lines and PDX models tested. This divergent behavior was reflected in the ability of lestaurtinib to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3, whereas ruxolitinib failed to block S727. Consistent with these findings, lestaurtinib additionally inhibited the serine/threonine kinases, JNK and ERK, leading to more complete suppression of STAT phosphorylation. Concordantly, combinatorial treatment with ruxolitinib and a JNK or ERK inhibitor resulted in synergistic antineoplastic effects at dose levels where the single agents were ineffective. Taken together, these findings indicate that lestaurtinib, and other treatments that converge on JAK/STAT signaling, are worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer.

Peptide-Drug Conjugates: A New Hope for Cancer.

Peptide-drug conjugates (PDCs) are advancing as targeted cancer therapies, leveraging lessons from antibody-drug conjugates (ADCs) to improve tumour specificity. These molecules combine a homing peptide with a cytotoxic payload via a linker, enabling precise drug delivery while sparing healthy tissue. Despite their potential, PDCs face challenges including metabolic instability, premature payload release and rapid clearance, limiting clinical success. Only Lutathera remains FDA-approved after Pepaxto's withdrawal, though Pepaxto retains EMA and MHRA approval-highlighting regulatory and technical complexities. Most PDCs target overexpressed receptors (e.g., somatostatin and GnRH), though novel designs like CBX-12 employ alternative strategies. Currently, six PDCs are in Phase III trials, with ~96 in development, signalling growing interest. This review explores how ADC research has guided PDC optimisation, particularly in linker chemistry and payload selection. We analyse key structural features governing PDC efficacy, including peptide-receptor binding and intracellular trafficking. Innovations in stable linkers and tumour-selective activation mechanisms are critical to overcoming pharmacokinetic hurdles. Promising candidates in late-stage trials are highlighted, emphasising their potential to address unmet needs in oncology. By refining targeting precision and payload delivery, next-generation PDCs may expand treatment options for resistant cancers, bridging the gap between biologics and small-molecule therapies.

Enhanced sensitivity, robust p21 activation, and sustained DNA repair responses to interstrand crosslinks in elephant cells compared to humans

Elephants exhibit remarkable resistance to cancer, and understanding these mechanisms has focused on their potential applications in cancer prevention and treatment in humans. A genome-wide comparative analysis identified that the accelerated regions in elephants are enriched in Fanconi anemia (FA) complementation group L (FANCL), a ubiquitin E3 ligase that mediates the monoubiquitylation of FANCD2 as an essential step in the FA pathway. The FA pathway plays a crucial role in DNA interstrand crosslink (ICL) repair, contributing substantially to genome stability and cancer resistance. In this study, we investigated the differences in ICL repair via the FA pathway, including the function of FANCL, as well as the DNA damage response to ICLs between elephants and humans. We found that elephant fibroblasts exhibited higher sensitivity to ICL-inducing treatments, such as mitomycin C and trimethylpsoralen plus UVA (PUVA), than human fibroblasts, while showing comparable or reduced sensitivity to other DNA-damaging agents, such as doxorubicin and bleomycin. Functional analyses revealed that elephant and human FANCL performed similarly in mediating FANCD2 monoubiquitylation and cell viability following mitomycin C treatment. Interestingly, elephant fibroblasts exhibited a more potent and prolonged activation of p21 and sustained DNA repair responses, such as FANCD2 monoubiquitylation and increased RAD51expression, following ICL-induced treatments. Moreover, elephant fibroblasts showed significantly greater RAD51 foci formation than human fibroblasts after PUVA treatment, even under comparable levels of DNA damage. These findings suggest that elephants efficiently repair ICLs in growth-arrested cells likely through robust p21 activation. This study provides new insights into the cancer resistance mechanisms of elephants and offers novel approaches for cancer prevention and therapy.

NASP implication in the androgen receptor associated with castration resistance in prostate cancer

Uncovering the mechanisms underlying tumor malignancy is extremely important for cancer treatment and management. In this study, using a pairwise cell model, LNCaP and its castration-resistant derivative C42B, we analyze the function of enhanced NASP protein in castration resistance. The data show that the expression of androgen receptor-targeted genes was obviously affected by NASP knockdown in C42B cells, and nearly 20% of the differential genes were AR dependent. ATAC-seq analysis revealed that NASP knockdown in C42B cells comprehensively increased chromatin accessibility, and disorders at AR occupancy regions were more prominent. Castration-induced genes, especially androgen-independent AR target genes, were enriched in the downregulated gene group. Further analysis of high-order chromatin interactions revealed that NASP knockdown in C42B led to frequent changes in multiple layers, including the compartment A/B transition, TAD boundary distance and chromatin loop, and AR-binding regions especially underwent more extensive reconstruction. Finally, we found that the recovery of the histone H3 pool in C42B can actually recall H3 back to the previous regions with both H3 and AR loss induced by NASP knockdown, but AR rebinding to the corresponding sites is obviously inhibited and lagging. These data indicate that NASP plays a fundamental role in guarding proper and fine mechanisms of AR in prostate cancer promotion and malignancy.

An enzyme-responsive hydrogel functionalized with mesoporous silica nanoparticles for co-delivery of cisplatin and shRNA to overcome chemotherapy resistance in non-small cell lung cancer

Chemoresistance poses a critical challenge in cancer therapy across diverse tumor types, including non-small cell lung cancer (NSCLC), where chemotherapy-induced neuroendocrine differentiation (NED) of tumor cells plays a pivotal role in acquiring treatment resistance. This process significantly reduces chemotherapy efficacy, accelerates tumor progression, and ultimately worsens patient survival outcomes. The complex mechanisms underlying chemoresistance involve multiple factors, including enhanced DNA repair pathways, increased drug efflux capacity, and alterations in gene expression. Additionally, the tumor microenvironment, a dynamic ecosystem surrounding cancer cells, fosters a protective niche that exacerbates chemotherapy resistance. To address this challenge, we propose an innovative nanocomposite hydrogel system for the co-delivery of cisplatin and short hairpin RNA (shRNA) targeting protein arginine methyltransferase 5 (PRMT5), a key gene implicated in drug resistance. This system utilizes polyethyleneimine-modified mesoporous silica nanoparticles, which serve as nanocarriers, encapsulating cisplatin within the mesopores and coating the surface with methacryloylated hyaluronic acid (HA-MA). The design enables tumor microenvironment-responsive drug release, triggered by hyaluronidase enzymes abundant within the tumor, resulting in nanoparticle disassembly and the release of cisplatin. Simultaneously, the delivery of shRNA silences PRMT5 expression, enhancing chemosensitivity. By integrating targeted gene therapy with chemotherapy, this system offers a promising strategy for overcoming chemoresistance in NSCLC. Targeting both cancer cells and their microenvironment, this approach holds potential to transform the treatment of chemotherapy-resistant cancers, advancing more effective and personalized oncological therapies.

Prognostic value of systemic inflammatory markers in predicting neoadjuvant platinum response and platinum resistance in advanced epithelial ovarian cancer: A peritoneal cancer index-based analysis.

Prognostic value of systemic inflammatory markers in predicting neoadjuvant platinum response and platinum resistance in advanced epithelial ovarian cancer: A peritoneal cancer index-based analysis.

Long non-coding RNA MINCR silencing contributes to suppressed gemcitabine resistance in bladder cancer by blocking the ZEB1/PHGDH axis through microRNA-876-5p up-regulation.

Long non-coding RNA MINCR performs a tumor-promoting role in various cancers. Accordingly, this research analyzed whether MINCR exerted tumor-promoting effects and facilitated gemcitabine (GEM) resistance in BC. MINCR, microRNA (miR)-876-5p, ZEB1, and PHGDH expression was detected in BC tissues and cells. Following the construction of GEM-resistant cells, MINCR expression was examined with RT-qPCR. Gain- and loss-of-function assays were conducted in GEM-resistant cells, followed by the measurement of cell proliferation, invasion, and apoptosis. The relationships among MINCR, miR-876-5p, and ZEB1 were assessed with dual-luciferase and RIP assays. Subcutaneous tumor formation in nude mice was conducted for in vivo corroboration. MINCR was up-regulated in BC tissues and cells and GEM-resistant BC cells. miR-876-5p expression was poor and ZEB1 and PHGDH expression was abundant in BC tissues. Mechanistically, MINCR enhanced ZEB1 expression in BC cells via competitive binding to miR-876-5p, and ectopic ZEB1 induced PHGDH up-regulation. MINCR silencing diminished proliferation and invasion while accelerating apoptosis in GEM-resistant BC cells, which was further advanced by miR-876-5p overexpression but nullified by ZEB1 overexpression. Meanwhile, MINCR silencing or miR-876-5p overexpression synergized with GEM to depress BC growth in vivo. MINCR silencing impedes GEM resistance in BC through the miR-876-5p/ZEB1/PHGDH axis.

Live-Cell NanoBRET Assay to Measure AKT Inhibitor Binding to Conformational States of AKT.

AKT is the main protein kinase of the PI3K-AKT pathway, interacting with over one hundred protein partners to facilitate cellular processes that allow cancer cells to survive and proliferate. It is an attractive target due to its control over many cellular outputs. However, ATP-competitive and allosteric AKT inhibitors have performed poorly in clinical trials. AKT inhibitor interactions with AKT are multifaceted and influence the catalytic activity of AKT, its conformation, its ability to interact with binding partners, and its phosphorylation state. Therefore, a better understanding of how these inhibitors influence these parameters is needed, especially in a cellular context. Using a live-cell NanoBRET target engagement assay to query the binding of AKT inhibitors to all isoforms of AKT, we found that ATP-competitive inhibitors bind similarly across all three isoforms and allosteric inhibitors bind more heterogeneously. Further, assaying gain-of-function pathological mutants and myristoylated active versions of all AKT isoforms revealed that T308 phosphorylation enhances the binding of ATP-competitive inhibitors. We found that this phosphorylation is a good indicator of cell viability sensitivity to ATP-competitive inhibitors when comparing effects on known resistant and sensitive triple-negative breast cancer cell lines. Taken together, these findings are useful for screening new AKT inhibitors, and these findings represent important considerations in developing the next generation of AKT inhibitors.

Integrated Nanopore and short-read RNA sequencing identifies dysregulation of METTL3- m6A modifications in endocrine therapy- sensitive and resistant breast cancer cells

The role of epitranscriptomic changes in the development of acquired endocrine therapy (ET)- resistance in estrogen receptor α (ER) expressing breast cancer (BC) is unknown. We tested the hypothesis that inhibition of METTL3, the methyltransferase responsible for the mRNA modification N-6 methyladenosine (m6A), alters m6A modifications and differentially regulates the abundance of mRNA transcripts in ET-sensitive MCF-7 versus resistant LCC9 ER + human BC cells. Differential m6A modifications were identified using direct mRNA sequencing (DRS) performed on five replicates for each cell line ± 1 µM STM2457, a selective METTL3 inhibitor, using Nanopore MinION long read RNA-seq. Parallel short read Illumina RNA-seq quantified differential transcript abundance in the same samples. Selected results were validated by RT-qPCR, m6A-RIP-qPCR, reporter assays, and western blot analysis. Statistical analysis combined m6Anet, a machine-learning algorithm designed to call m6A modified bases, with a generalized linear model following a binomial distribution analysis to identify significant differential m6A modification ratios (DMR). Distinct METTL3 dependent m6A modification patterns in LCC9 and MCF-7 cells were observed in differentially expressed genes (DEG) associated with ET-resistance, including EEF1A2, ACTB, FLNA, PDIA6, AMIGO2, TPT1, XBP1, and CITED4. Select results were validated in additional ET-resistant BC cell lines. m6A-RIP-RT-qPCR validated specific m6A sites. We examined the proximity of m6A sites to estrogen receptor α (ER α)-mRNA binding sites reported in MCF-7 cells. ACTB, PDIA6, and XBP1 demonstrated a short-range proximity, with m6A sites located within 100 bp of ERα binding sites, suggesting a role for m6A in influencing ERα-mRNA binding. Our work provides a framework for integrating DRS and DEG omics data. Our results suggest a role for dysregulation of m6A modifications in pathways implicated in ET resistance in BC.

Spinal analgesia in cancer pain management-MASCC general practice recommendations.

Patients with cancer pain refractory to conventional medical management may benefit from spinal analgesia, although there are some critical points regarding some aspects which cannot be examined by an evidence-based approach. A group of experts was selected by MASSC to provide clinical practice advice on the use of spinal drug delivery in patients with cancer-related pain. Refractory cancer pain should be considered a condition in which a patient has failed to receive adequate analgesia or has developed uncontrolled side effects after comprehensive pain management. The intrathecal route (IT) with an implantable drug delivery system allows the administration of minimal doses of analgesics with significant clinical effects while avoiding major adverse effects and lower risks with prolonged use. Morphine and hydromorphone are the opioids of choice for IT treatment. Local anesthetics are an added value because of their additive-synergic effect on segmental areas. The efficacy of adding small amounts of local anesthetics to an ITDD relies on the positioning of the tip of the catheter close to the dermatome where the origin of the pain comes from. Their use, however, depends on the delivery system, because larger volumes are necessary. Ziconotide requires a slow dose titration, but it can be used in small volumes. In addition, once doses are stabilized, no tolerance occurs. A conversion ratio of 100:1 between oral and IT morphine is suggested for patients who receive high doses of systemic opioids. A higher ratio (300:1) should be used in patients prevalently switched to the IT route for uncontrollable adverse effects, receiving lower doses of systemic opioids. The use of boluses of hydrophilic opioids, like morphine, for treating breakthrough pain may be inadequate, as intrathecal opioids alone may be unable to adequately treat an episode of rapid pain onset and duration. The decision-making process for employing interventional therapies, like spinal analgesia, should be shared, taking into account the actual indications and needs, previous treatments, prognosis, timing, advantages and disadvantages, and complications, in any individual situation, managing all the aspects of care.

Do turtles get cancer?

Abstract Turtles are renowned for their extreme longevity and tremendous range in body size. Theoretically, large, long-lived organisms should face higher cancer risks because of increased cell numbers and lifetime cellular turnover, yet cancer appears to be exceptionally rare in turtles. In the present article, we synthesize the current knowledge on cancer prevalence in turtles, drawing from zoo necropsies, pathology reports, and comparative oncology studies, and present new data spanning additional species that reinforce this pattern. Emerging molecular evidence suggests that turtles possess high resistance to oxidative stress and protein dysregulation, which may contribute to cancer resistance. Given their extreme lifespans and unique physiology, turtles represent a promising but underexplored model for studying the evolution of longevity and natural cancer suppression mechanisms.

Cascade‐Targeted Nanoparticles for Enhanced Gemcitabine Delivery and Adenosine Metabolism Modulation to Overcome Treatment Resistance in Pancreatic Cancer

Abstract KRAS mutations are find in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases, making PDAC exhibit intrinsic resistance to chemotherapy and reshape the immunosuppressive tumor microenvironment (TME), disappointing the clinically preferred chemotherapy‐immunotherapy combination. Standing on the cross point of therapeutic resistance, the aberrant adenosine metabolism contributes greatly to chemo‐ and immunotherapy tolerance. KRAS mutation‐induced over‐expression of key enzyme CD39 is believed to be involved in shaping the immunosuppressive TME, as it catalyzes the hydrolysis of extracellular ATP into immunosuppressive adenosine. Meanwhile, the loss of equilibrative nucleoside transporters (ENTs) leads to the accumulation of adenosine and the intracellular delivery difficulty of gemcitabine, further vanishing patients’ hope of benefiting from either chemotherapy or immunotherapy. The key challenge is to modulate the aberrant metabolism, also enhance gemcitabine intracellular delivery. Therefore, ROS‐responsive positively‐charged polymer B‐PDEA is prepared and assembled into polyplexes for loading CD39‐down‐regulating small interfering RNA. Gemcitabine‐loaded albumin is coupled with the polyplexes through enzyme‐cleavable peptide, forming the intact nanoparticles for the co‐delivery of the first‐line chemotherapeutic drug and CD39‐regulating nucleic acid, showing enhanced gemcitabine intracellular delivery and adenosine metabolism regulating capacity. This approach activated antitumor immunity while achieving chemosensitization by changing the metabolic‐immune crosstalk of TME, showcasing great potential for PDAC treatment.

High Co-Expression of GPAT4 and SLC7A11 as a Predictor of Platinum Resistance and Poor Prognosis in Patients with Epithelial Ovarian Cancer

Background/Objectives: This study aimed to determine whether the expression levels of GPAT4 and SLC7A11 are associated with survival outcomes and platinum resistance in epithelial ovarian cancer (EOC) patients. Methods: We analyzed the medical records of EOC patients. EOC samples obtained during surgery were stained for GPAT4 and SLC7A11. Cox regression and Kaplan—Meier analyses were performed to assess the impact of GPAT4 and SLC7A11 expression on overall survival (OS). Results: We found that GPAT4 and SLC7A11 expression levels were greater in platinum-resistant ovarian cancer tissues than in platinum-sensitive ovarian cancer tissues. High expression of both GPAT4 and SLC7A11 was associated with an increased risk of platinum resistance compared with low expression of both factors. High expression of both SLC7A11 and GPAT4 was independently correlated with poor OS, highlighting the significance of this integrated metric as a prognostic factor in ovarian cancer. The GPAT inhibitor (GPAT-IN-1) and an SLC7A11 inhibitor (erastin) attenuated platinum resistance in ovarian cancer cells, and their combined application increased cytotoxicity. Furthermore, the combination of GPAT-IN-1, erastin, and cisplatin significantly improved the chemotherapeutic effects on platinum-resistant ovarian cancer cells. Conclusions: High expression of both SLC7A11 and GPAT4 is related to platinum resistance in EOC patients. The high expression of both SLC7A11 and GPAT4 serves as an important independent prognostic factor and indicates potential therapeutic targets for patients with platinum-resistant EOC.

Novel diagnostic and therapeutic strategies based on PANoptosis for hepatocellular carcinoma

Hepatocellular carcinoma (HCC), a highly aggressive liver cancer, poses a large medical care burden worldwide. The prognosis of patients with HCC is poor, owing to recurrence and metastasis after common treatment methods. Therefore, identifying new targets to eliminate HCC cells is critical for treatment of HCC without recurrence. PANoptosis, a novel inflammatory cell death pathway, has become an intensively investigated area in recent years. The concept of PANoptosis has brought new hope for HCC therapy, given recent evidence implicating this form of programmed cell death in cancer progression, prognosis, and resistance to chemotherapy and immunotherapy. Despite increasing reviews describing the role of PANoptosis in various cancer types, to our knowledge, no systematic review has examined the implications of PANoptosis in HCC. Therefore, we sought to provide the first systematic review of the regulatory mechanisms and therapeutic potential of PANoptosis in HCC. We summarize recent progress in exploration of the role of PANoptosis in HCC, particularly regulation of the HCC tumor microenvironment by PANoptosis. Finally, we highlight the potential of PANoptosis-based diagnostic and therapeutic strategies for HCC.

Wnt Signaling and Circular RNAs in Esophageal and Gastric Cancers: Opportunities for Early Detection and Targeted Therapy.

Aberrant activation of Wnt/β-catenin signaling, frequently caused by oncogenic mutations, plays a crucial role in the development, progression, and therapy resistance of gastric, esophageal, hepatic, pancreatic, and colorectal cancers. Concurrently, circular RNAs (circRNAs), produced by back-splicing of precursor mRNAs (pre-mRNAs), have emerged as critical modulators of this pathway. Accumulating evidence indicates that specific circRNAs regulate Wnt/β-catenin signaling by sponging microRNAs, interacting with RNA-binding proteins, modulating protein function, and altering the expression of pathway components. Some circRNAs are also subject to feedback regulation by Wnt signaling itself. Clinically, tumor-associated circRNAs are present in body fluids and correlate with disease stage, metastatic burden, and patient survival, underscoring their potential as early and minimally invasive biomarkers. Moreover, targeting oncogenic circRNAs has shown promise in preclinical models of Wnt-driven gastrointestinal malignancies. In this review, we summarize the current understanding of the interplay between circRNAs and Wnt/β-catenin signaling in gastric and esophageal cancers. We discuss the translational challenges and emerging opportunities for biomarker development and targeted therapy.

Prognostic Value of a Joint K‐PD Model With Tumor Size Dynamics and CA‐125 Kinetics in Recurrent Ovarian Cancer Patients: BOLD Phase II GINECO Study

ABSTRACTIn patients with recurrent advanced ovarian cancer, there is a need for companion tests to guide the development of innovative chemotherapy‐free treatments. The modeled longitudinal CA‐125 ELIMination rate constant K KELIM‐B was a major prognostic factor for progression‐free survival (PFS) and overall survival (OS) in recurrent advanced ovarian cancer patients treated with bevacizumab, olaparib, and durvalumab in the BOLD trial. The objective was to determine if a joint semi‐mechanistic model with tumor size and CA‐125 kinetics would increase KELIM‐B accuracy/prognostic value. The BOLD phase II trial (NCT04015739) investigated the triplet regimen in 74 patients with recurrent platinum‐sensitive/resistant advanced ovarian cancer. Two kinetic‐pharmacodynamic models were developed to fit the data collected during the first 100 treatment days: (1) a CA‐125 longitudinal kinetics model, and (2) a joint model integrating both CA‐125 kinetics and tumor size. The prognostic value of KELIM‐B and KELIM‐joint was assessed using univariate/multivariate analyses (PFS/OS). The modeling of CA‐125 and tumor size dynamics was feasible with adequate quality checks. The prognostic value of the categorical KELIM‐joint, binarized by the median (PFS, HR = 0.29, 95% CI [0.12–0.72]; OS, HR = 0.24, 95% CI [0.08–0.74]), was not clinically different from that of KELIM‐B (PFS, HR = 0.35, 95% CI [0.14–0.84]; OS, HR = 0.34, 95% CI [0.12–0.99]). Interactions between tumor size changes and CA‐125 kinetics could be assessed in the joint model. However, the improvement in prognostic value was not sufficient to justify the higher complexity of the joint model. Assessing early longitudinal CA‐125 kinetics alone remains the best pragmatic strategy for future development.

Efficacy and Safety of Chemotherapy Combined with Anlotinib in Advanced EGFR-mutant NSCLC with Primary Resistance to EGFR-TKIs：a retrospective cohort Study

Objective: To explore effective treatment strategies for EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitors) primary resistant advanced non-small cell lung cancer (NSCLC). Methods: We collected data on the efficacy and safety of chemotherapy combined with anlotinib in patients with EGFR-TKI primary resistant advanced NSCLC. The primary endpoints of this study were overall response rate (ORR), progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and treatment-related adverse events (AEs). Results: A total of 34 patients were enrolled. The preliminary results demonstrate that ORR and DCR of chemotherapy combined with anlotinib in patients with EGFR-TKI primary resistant advanced NSCLC were 32.35% and 64.71%, respectively. The median PFS and OS were 5 months and 9 months, respectively. In addition to efficacy, common adverse effects included myelosuppression, hypertension, proteinuria, and hand-foot syndrome. These were generally mild and well-tolerated, indicating that this regimen has promising prospects for overcoming EGFR-TKI primary resistance in advanced NSCLC. Conclusion: The combination of chemotherapy and anlotinib shows promising efficacy in patients with primary EGFR TKI-resistant advanced NSCLC, with a manageable safety profile. This regimen offers a potential new treatment option for this challenging patient population. Further studies are warranted to confirm these findings and explore long-term outcomes.

Rhabdomyolysis induced by darolutamide and rosuvastatin.

Introduction: Darolutamide is a second-generation nonsteroidal androgen receptor antagonist approved for treatment of castrate-resistant, nonmetastatic prostate cancer and metastatic hormone-sensitive prostate cancer. Case report: A mid-70s man with castration-resistant prostate cancer was initiated on darolutamide. Due to impaired renal function and a history of poor tolerance to previous chemotherapy, the patient was started at 300 mg per day with a plan to titrate to the recommended renal-adjusted dose. He was admitted to the hospital for complaints of lower extremity weakness during week 11 of treatment. Physical examination and imaging did not indicate any significant pathology from cancer or other medical conditions causing his symptoms. The pharmacist identified and reported a significant drug interaction between darolutamide and rosuvastatin. Management & Outcome: The suggested change was rosuvastatin discontinuation. Limiting the rosuvastatin dose to 5 mg is recommended during concomitant use with darolutamide. Since the patient had been receiving rosuvastatin 40 mg daily, he was potentially receiving five times the maximum dose. Considering the patient's complaints of myalgia and a marked elevation in creatine phosphokinase, his condition confirmed the diagnosis of rosuvastatin-darolutamide-induced rhabdomyolysis. Clinical symptoms improved and creatinine phosphokinase (CPK) elevation subsided following rosuvastatin cessation. Discussion: Darolutamide inhibition of breast cancer resistance protein (BCRP), organic anion-transporting polypeptides (OATP), and other protein transporters impacts clearance of substrate drugs to varying extents. Clinical relevance of inhibition depends on the extent to which affected proteins and transporters contribute to the clearance of the substrate. Rosuvastatin's significant reliance on BCRP for active efflux leads to an elevated risk of statin-associated muscle symptoms when co-administered with darolutamide.