Receptor Mutations Research Articles

Pharmacological effects of osimertinib on a chicken chorioallantoic membrane xenograft model with the EGFR exon-19-deleted advanced NSCLC mutation.

Non-small cell lung cancer (NSCLC) affects 10-50% of patients with epidermal growth factor receptor (EGFR) mutations. Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) that radically changes the outcome of patients with tumors bearing EGFR sensitizing or EGFR T790M resistance mutations. However, resistance usually occurs, and new therapeutic combinations need to be explored. The chorioallantoic membrane (CAM) xenograft model is ideal for studying aggressive tumor growth and the responses to complex therapeutic combinations due to its vascularization and complex microenvironment. This study aims to demonstrate the relevance of analyzing a complex therapeutic response to osimertinib treatment, especially through advanced transcriptomic analysis with the CAM model, which has been limited thus far. We engrafted HCC827 cells (EGFR p.E746_A750del) into the CAM model and treated them with various osimertinib doses for 7 days. The study involved supervised multivariate discrimination and ontology analysis of human transcriptional data. We found that CDX tumor growth inversely correlated with osimertinib dosage, with a notable 35% tumor weight reduction at 10 μm. Transcriptomic analysis revealed that osimertinib reduces EGFR pathway activity and its effectors, and dampens chemotaxis, immune recruitment and angiogenesis, indicating that effectiveness extends beyond cellular mechanisms to the tissue level. This was supported by a 15% reduction in blood vessels around the xenograft in osimertinib-treated cases. This study is the first to demonstrate that ontological analysis of transcriptomic data in the CAM model aligns with clinical observations, highlighting the relevance of this methodology for understanding and ameliorating the efficacy of targeted therapy in NSCLC.

Lipid Levels and Lung Cancer Risk: Findings from the Taiwan National Data Systems from 2012 to 2018

BackgroundLipids are known to be involved in carcinogenesis, but the associations between lipid profiles and different lung cancer histological classifications remain unknown.MethodsIndividuals who participated in national adult health surveillance from 2012 to 2018 were included. For patients who developed lung cancer during follow-up, a 1:2 control group of nonlung cancer participants was selected after matching. Multivariate conditional logistic regression was used to explore the associations between lipid profiles, different lung cancer histological classifications and epidermal growth factor receptor mutation statuses. Subgroup, sensitivity, and dose‒response analyses were also performed.ResultsA total of 4,704,853 participants (30,337 lung cancer participants and 4,674,516 nonlung cancer participants) were included. In both the main and sensitivity analyses, the associations remained constant between lower high-density lipoprotein (HDL) cholesterol levels and a higher risk of lung cancer (main analysis: odds ratio: 1.13 [1.08–1.18]) and squamous cell carcinoma (1.29 [1.16–1.43]). Hypertriglyceridemia was associated with a lower risk of adenocarcinoma (0.90 [0.84–0.96]) and a higher risk of small cell lung cancer (1.31 [1.11–1.55]). Hypercholesterolemia was associated with a lower risk of squamous cell carcinoma (0.84 [0.76–0.94]). In the subgroup analysis, lower HDL cholesterol levels were associated with greater risk across most subgroups. HDL cholesterol levels also demonstrated a dose‒response association with the development of lung cancer.ConclusionsThe distinct associations between specific lipid profiles and lung cancer subtypes suggest that lipid metabolism may play different mechanistic roles in lung cancer development.

Optimizing Osimertinib for NSCLC: Targeting Resistance and Exploring Combination Therapeutics

Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, with epidermal growth factor receptor (EGFR) mutations present in a substantial proportion of patients. Third-generation EGFR tyrosine kinase inhibitors (EGFR TKI), exemplified by osimertinib, have dramatically improved outcomes by effectively targeting the T790M mutation—a primary driver of acquired resistance to earlier-generation EGFR TKI. Despite these successes, resistance to third-generation EGFR TKIs inevitably emerges. Mechanisms include on-target mutations such as C797S, activation of alternative pathways like MET amplification, histologic transformations, and intricate tumor microenvironment (TME) alterations. These resistance pathways are compounded by challenges in tolerability, adverse events, and tumor heterogeneity. In light of these hurdles, this review examines the evolving landscape of combination therapies designed to enhance or prolong the effectiveness of third-generation EGFR TKIs. We explore key strategies that pair osimertinib with radiotherapy, anti-angiogenic agents, immune checkpoint inhibitors, and other molecularly targeted drugs, and we discuss the biological rationale, preclinical evidence, and clinical trial data supporting these approaches. Emphasis is placed on how these combinations may circumvent diverse resistance mechanisms, improve survival, and maintain a favorable safety profile. By integrating the latest findings, this review aims to guide clinicians and researchers toward more individualized and durable treatment options, ultimately enhancing both survival and quality of life for patients with EGFR-mutated NSCLC.

P-1066. Quorum Sensing Coordinates Phage Defense Mechanisms in Pseudomonas aeruginosa

Abstract Background Quorum sensing (QS) plays a crucial role in regulating key traits, including the upregulation of phage receptors, leading to heightened phage susceptibility in Pseudomonas aeruginosa. Consequently, elevated cell densities usually escalate the likelihood of phage invasions. This observation has sparked speculation that bacteria might have evolved multiple antiphage defense mechanisms to offset the cost of increased phage receptor expression during the prolonged coevolution or cohabitation with phages. The impact of cell-free supernatant on phage-host interactions in liquid medium was investigated. (A) Growth curves of ZS-PA-35 and (B) corresponding phage concentrations measured in plaque forming units (PFU) per milliliter, in the presence or absence of phage phipa2 or phipa10 at Multiplicity of Infection (MOI) of 2. Measurements were taken at 1-h intervals over a 6-hincubation period in conditioned medium. The conditioned medium was derived from high-cell density cultures of strain ZS-PA-35 and supplemented with 25% 4 × LB medium. Error bars depict standard deviations (n=3). Methods The role of QS in defense strategies employed by P. aeruginosa to fight against phages phipa2 and phipa10’s predation was determined by comparing phage inhibition, adsorption, and resistance assays between ZS-PA-35 and its QS mutants (ΔlasR, ΔrhlR, ΔlasI, ΔrhlI, ΔlasR ΔrhlR, and ΔlasI ΔrhlI) at low- and high-cell-densities. QS regulates phage-host interactions in liquid medium. In LCD cultures, optical densities (OD600) and corresponding phage concentrations of P. aeruginosa wild-type (ZS-PA-35) and QS mutants (ΔlasR, ΔrhlR, ΔlasI, ΔrhlI, ΔlasR ΔrhlR, and ΔlasI ΔrhlI) were determined with phage phipa2 or phipa10 at MOIs of 0.01. In HCD cultures, similar measurements were taken at 2-h intervals over an 8-h period. Error bars represent standard deviations (n=3). Results The Las system increases phage adsorption rates by upregulating the expression of Type IV pilus and O-antigen receptors, which subsequently leads to accelerated bacterial lysis. Moreover, the Las system, apart from mediating receptor mutations, orchestrates an additional intracellular defense mechanism to suppress the production of both phage phipa2 and phipa10, resulting in a reduction of over 2 logs in high cell density cultures of strain ZS-PA-35 and phipa10. These flexible regulatory systems optimize the function of various defense strategies, particularly when bacterial communities are most susceptible to phage invasion. QS regulates phage adsorption. Adsorption assays were conducted to assess the interaction between phage phipa2 (A and B) or phipa10 (C and D) and its host strain ZS-PA-35, as well as QS mutants, under low cell density (LCD) conditions (A and C) and high cell density (HCD) conditions (B and D). The data represent averages from three independent samples, with error bars indicating standard deviations. Statistical significance was determined using ordinary one-way ANOVA with Dunnett’s test, with significance levels indicated as *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Significant results are highlighted accordingly. Conclusion Bacteria employ QS to finely tune various defense strategies, both mutational and non-mutational defense mechanisms, highlighting the intricate nature of phage-host interactions and the challenges associated with the potential clinical use of phages as therapeutic agents. Statistical significance is indicated as *P < 0.05, ***P < 0.001, ****P < 0.0001 (one-way ANOVA), with all significant findings appropriately highlighted. Disclosures All Authors: No reported disclosures

Effect of SMARCA4 mutations on the outcomes of patients with advanced EGFR mutant lung adenocarcinoma

Objective: To investigate the impact of SMARCA4 mutations on the outcomes of patients with advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Methods: In the Memorial Sloan Kettering Cancer Center (MSK) MetTropism study, 960 patients with advanced EGFR-mutated lung adenocarcinoma were screened and included in the MSK cohort, composing of 313 males and 647 females, with a median [M(Q1, Q3)] age of 64 (56, 72) years. A retrospective analysis was conducted on the data of 178 patients with advanced EGFR-mutated lung adenocarcinoma who received EGFR tyrosine kinase inhibitors (TKIs) treatment in the Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, from January 2018 to December 2022. Among these patients, 69 were males and 109 were females, with a median age of 63 (54, 69) years. The follow-up of patients from the First Affiliated Hospital of Nanjing Medical University was conducted up to December 31, 2023, with a median follow-up time of 26.6 (95%CI: 24.6-28.6) months for the entire cohort, and 29 patients were lost to follow-up. Survival curves were plotted using the Kaplan-Meier method, and the log-rank test was used to compare the relationship between SMARCA4 gene alternations and prognosis. Results: In the 960 patients of the MSK cohort with advanced EGFR-mutated lung adenocarcinoma, the SMARCA4 gene alternations rate was 4.2% (40/960). The median overall survival (OS) for patients without SMARCA4 gene alternations was 41.5 (95%CI: 35.6-47.3) months, which was superior to that of patients with SMARCA4 gene alternations [15.6 (95%CI: 7.9-23.4) months, P<0.001]. Patients with SMARCA4 gene alternations had a higher risk of mortality, with an HR (95%CI) of 1.97 (1.35 to 2.88). Among the 178 patients with advanced EGFR-mutated lung adenocarcinoma from the First Affiliated Hospital of Nanjing Medical University, the SMARCA4 gene alternations rate was 4.5% (8/178). The median progression-free survival (PFS) for patients without SMARCA4 gene alternations was 16.1 (95%CI: 12.2-20.0) months, which was superior to the median PFS of patients with SMARCA4 gene alternations [6.0 (95%CI: 1.3-10.7) months, P<0.001]. The median OS for patients without SMARCA4 gene alternations was 50.1 (95%CI: 28.1-72.1) months, which was also superior to the median OS of patients with SMARCA4 gene alternations [17.6 (95%CI: 15.4-19.8) months, P=0.001]. Conclusion: SMARCA4 alternation is an important factor associated with poor prognosis in patients with advanced EGFR-mutant lung adenocarcinoma.

Suitability of different cytological preparations for molecular analysis of advanced NSCLC.

Around 85% of non-small cell lung cancers (NSCLCs) are diagnosed at an advanced stage (IIIB to IV), where therapeutic options depend on molecular analysis. However, diagnostic material for molecular testing is often represented by cytological samples which are generally scarce and span a wide range of preparation types. Thus, the primary objective is to efficiently manage materials for molecular profiling. This study aims to evaluate the suitability of different cytological samples to assess morphological and molecular characteristics of advanced NSCLC. Sixty-seven cytological samples obtained from patients with advanced NSCLC were utilized. The series encompassed different procedure types (fine-needle aspiration cytology, transbronchial needle aspiration, effusions) processed by cell blocks in 54% (n=36), direct smears in 33% (n=22), and Liquid Based Cytology (LBC) in 13% (n=9). Cytological diagnoses were routinely performed and molecular analysis were conducted using NGS and RT-PCR methods. Adequate quantity and quality of nucleic acids were obtained from all the samples, allowing molecular profiling. Combined Next Generation Sequencing (NGS) and Real Time-Polymerase Chain Reaction (RT-PCR) analysis showed wild-type profiles in 62.7% (n=42) and mutated profiles in 37.3% (n=25) of the samples. Kirsten Rat Sarcoma Virus (KRAS) mutations were identified in 19.5% (n=13) of samples, Epidermal Growth Factor Receptor (EGFR) mutations in 10.4% (n=7) and v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations in 2.9% (n=2). Identified chromosomal alterations were v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) duplication in 2,9% (n=2). The cytological sample types examined in this study proved to be suitable for molecular testing, in addition to conventional morphologic diagnosis, showing versatility and adaptability to different clinical contexts. Molecular testing on cytological samples is accurate and fast, representing a valid tool for molecular profiling of advanced NSCLC.

Exploiting YES1-driven EGFR expression improves the efficacy of EGFR inhibitors.

Epidermal growth factor receptor (EGFR) is a highly expressed driver of many cancers, yet the utility of EGFR inhibitors is limited to cancers that harbor sensitizing mutations in the EGFR gene due to dose limiting toxicities. Rather than conventionally blocking the kinase activity of EGFR, we sought to reduce its transcription as an alternative approach to broaden the therapeutic window for EGFR inhibitors targeting wildtype or mutant EGFR. We found that YES1 is highly expressed in triple negative breast cancer (TNBC) and drives cell growth by elevating EGFR levels. Mechanistically, YES1 stimulates EGFR expression by signaling to JNK and stabilizing the AP-1 transcription factor, c-Jun. This effect extends beyond TNBC as YES1 also sustains EGFR expression in non-small cell lung cancer (NSCLC) cells, including those that harbor the EGFR gatekeeper mutation, T790M. The novel ability of YES1 to regulate the expression of wildtype and mutant EGFR mRNA and protein provides a potential therapeutic opportunity of utilizing YES1 blockade to broadly increase the efficacy of EGFR inhibitors. Indeed, we found synergy within in vitro and in vivo models of TNBC and NSCLC, even in the absence of EGFR activating mutations. Together, these data provide a rationale for blocking YES1 activity as an approach for improving the efficacy of EGFR-targeting drugs in cancers that have generally been refractory to such inhibitors. Implications: YES1 sustains EGFR expression, revealing a therapeutic vulnerability for increasing the efficacy of EGFR inhibitors by lowering the threshold for efficacy in tumors driven by wildtype or mutant receptor.

Next generation sequencing (NGS)-based molecular panel analysis for metastatic prostate cancer: how often can we detect druggable mutations? : NGS for metastatic adenocarcinoma of the prostate

Prostate cancer guidelines recommend molecular analysis of biomaterial following resistance to first-line systemic therapy in order to identify druggable mutations. We report on our results of molecular analysis of tissue specimens via next generation sequencing (NGS) in men with metastatic castration resistant prostate cancer (mCRPC). In all, 311 mCRPC patients underwent NGS analysis from biopsy samples of progressive metastatic lesions or archival radical prostatectomy specimens. NGS analysis was either performed using a panel of 18 prostate cancer-specific amplicons or via the TS0500 panel. Of the 311 biopsies, 299 (96%) revealed sufficient DNA content for NGS analysis independent on the specimen origin. Biopsies were taken from prostate (31%), lymph nodes (26%), visceral (17%) or osseous (18%) metastases. In 223 (75%) and 76 (25%) patients activating/inhibiting and no mutations were identified, respectively. Most frequently, mutations of HRD genes including a positive HRD score and p53 were identified in 22% of patients each. About 50% of HRD gene mutations were pathogenic and treatment with PARP inhibitors was initiated. Although the majority of p53 alterations were inactivating mutations, 3 patients demonstrated gain-of-function mutations resulting in an inactivation of ATM. Activating androgen receptor mutations and inactivating PTEN mutations were identified in 42 (14%) and 24 (8%) patients, respectively. Specific AR mutations resulted in a switch of hormonal therapy. Mutations of mismatch repair deficiency genes/MSI high were identified in 5 patients resulting in the administration of pembrolizumab. Addition of the TSO 500 panel identified additional mutations in 4.5% of patients and only 2% of the total cohort would have benefitted from this large panel with the identification of druggable mutations. Druggable mutations were identified in one third of mCRPC patients using an 18 amplicon-panel analyzed via NGS. Based on our data, molecular analysis of AR mutations or mutations of the HRD genes should be performed following progression after first-line hormonal therapy. A more extensive molecular analysis seems to be useful following progression to the standard sequential hormonal, cytotoxicand radioligand therapies. Use of the expensive TSO 500 panel seems to be of additional therapeutic value in only a minority of patients.

Prediction of EGFR mutation status and its subtypes in non-small cell lung cancer based on 18F-FDG PET/CT radiological features.

Prediction of epidermal growth factor receptor (EGFR) mutation status and subtypes in patients with non-small cell lung cancer (NSCLC) based on 18F-fluorodeoxyglucose (18F-FDG) PET/computed tomography (CT) radiomics features. Retrospective analysis of 201 NSCLC patients with 18F-FDG PET/CT and EGFR genetic testing was carried out. Radiomics features and clinical factors were used to construct a combined model for identifying EGFR mutation status. Mutation/wild-type models were trained in a training cohort (n = 129) and validated in an internal validation cohort (n = 41) vs an external validation cohort (n = 50). A second model predicting the 19/21 mutation locus was also built and evaluated in a subset of EGFR mutations (training cohort, n = 55; validation cohort, n = 14). The predictive performance and net clinical benefit of the models were assessed by analysis of the area under curve (AUC) of the subjects, nomogram, calibration curve and decision curve. The AUC of the combined model distinguishing EGFR mutation status was 0.864 in the training cohort and 0.806 and 0.791 in the internal vs external test sets respectively, and the AUC of the 19/21 mutation site model was 0.971 and 0.867 in the training cohort and internal validation cohort respectively. The calibration curves of the individual models showed better model predictions (Brier score <0.25). Decision curve analysis showed that the models had clinical application. The combined model based on 18F-FDG PET/CT radiomics features combined and clinical features can predict EGFR mutation status and subtypes in NSCLC patients, and guiding targeted therapy, and facilitate precision medicine development.

Discovery of STX-721, a Covalent, Potent, and Highly Mutant-Selective EGFR/HER2 Exon20 Insertion Inhibitor for the Treatment of Non-Small Cell Lung Cancer.

After L858R and ex19del epidermal growth factor receptor (EGFR) mutations, ex20ins mutations are the third most common class of driver-mutations in non-small cell lung cancer (NSCLC). Unfortunately, first-, second-, and third-generation EGFR tyrosine kinase inhibitors (TKIs) are generally ineffective for ex20ins patients due to insufficient mutant activity and selectivity over wild-type EGFR, leading to dose-limiting toxicities. While significant advances in recent years have been made toward identifying potent EGFR ex20ins mutant inhibitors, mutant vs wild-type EGFR selectivity remains a significant challenge. STX-721 (53) is a potent, irreversible inhibitor of the majority of EGFR/HER2 ex20ins mutants and demonstrates excellent mutant vs wild-type selectivity both in vitro and in vivo. STX-721 is currently in phase 1/2 clinical trials for EGFR/HER2 ex20ins-driven NSCLC.

Impact of Bone-Modifying Agents on Post-Bone Metastasis Survival Across Cancer Types.

Bone metastasis is associated with a poor prognosis. Bone-modifying agents (BMA) are commonly used for the prevention or treatment of skeletal-related events (SRE) in patients with bone metastasis; however, whether or not treatment with BMA improves survival remains unclear. In this study, we investigated whether BMA was involved in post-bone metastasis survival. A total of 539 cancer patients were retrospectively analyzed to identify significant independent factors in post-bone metastasis survival. Among the overall population, patients with the following cancers had a median survival longer than 24 months: thyroid, 97.2 months; breast, 51.5 months; prostate, 47.2 months; and kidney, 38.8 months. In contrast, median post-bone metastasis survival was significantly shorter in gastrointestinal (GI) (6.5 months), head and neck (6.3 months), and urinary tract (3.4 months) cancers. In non-small cell lung cancer (NSCLC), the log-rank test demonstrated that the epidermal growth factor receptor (EGFR) mutation was a significant factor for post-bone metastasis survival: EGFR mutation (-) n = 67, median post-bone metastasis survival 11.5 months (95% CI: 6.0-15.2); EGFR mutation (+) n = 39, median post-bone metastasis survival 28.8 months (95% CI: 18.1-35.7) (p < 0.05). Intriguingly, treatment with BMA was a significant positive prognostic factor: BMA (-) n = 203, median post-bone metastasis survival 7.8 months (95% CI: 5.8-12.5); BMA (+) n = 336, median post-bone metastasis survival 21.9 months (95% CI: 16.1-26.4) (p < 0.001). Moreover, the Cox proportional hazards model showed that this was particularly evident in cancer types with poor prognosis such as GI cancer (hazard ratio [HR]: 0.62, 95% CI: 0.40-0.95; p < 0.05) and NSCLC without the epidermal growth factor receptor (EGFR) mutation (HR: 0.56, 95% CI: 0.34-0.91; p < 0.05). Treatment with BMA is recommended not only for the prevention and/or treatment of SRE, but also may have a positive impact on post-bone metastasis survival, particularly in cancers with typically poor post-bone metastasis survival such as GI cancer and NSCLC without the EGFR mutation.

Thyroid Hormone Resistance: A Case Report of a Novel Missense Thyroid Hormone Receptor (THR) Mutation

Thyroid Hormone Resistance: A Case Report of a Novel Missense Thyroid Hormone Receptor (THR) Mutation

Tissue-resident skeletal muscle macrophages promote recovery from viral pneumonia-induced sarcopenia in normal aging.

Sarcopenia, which diminishes lifespan and healthspan in the elderly, is commonly exacerbated by viral pneumonia, including influenza and COVID-19. In a study of influenza A pneumonia in mice, young mice fully recovered from sarcopenia, while older mice did not. We identified a population of tissue-resident skeletal muscle macrophages that form a spatial niche with satellite cells and myofibers in young mice but are lost with age. Mice with a gain-of-function mutation in the Mertk receptor maintained this macrophage-myofiber interaction during aging and fully recovered from influenza-induced sarcopenia. In contrast, deletion of Mertk in macrophages or loss of Cx3cr1 disrupted this niche, preventing muscle regeneration. Heterochronic parabiosis did not restore the niche in old mice. These findings suggest that age-related loss of Mertk in muscle tissue-resident macrophages disrupts the cellular signaling necessary for muscle regeneration after viral pneumonia, offering a potential target to mitigate sarcopenia in aging.

Understanding phage BX-1 resistance in Vibrio alginolyticus AP-1 and the role of quorum-sensing regulation.

The marine ecosystem is characterized by a rich diversity of bacterial hosts and their phages. The propagation of phages is primarily limited by their ability to adsorb to host cells and is further challenged by various bacterial defense mechanisms. To fully realize the potential of phage therapy in aquaculture, a comprehensive understanding of phage-host interactions and their regulation is essential. In this study, we isolated a novel Myoviridae phage, BX-1, capable of infecting Vibrio alginolyticus AP-1, and characterized its resistant mutants. We elucidated the essential role of the bacterial cellulose biosynthesis-related gene bcsE, which functions as a cyclic di-GMP-binding protein, in influencing host susceptibility to phage BX-1. Interestingly, Congo Red, Calcofluor White staining, and cellulose content assays indicated that deletion of bcsE in strain AP-1 does not completely abolish cellulose production, suggesting that bcsE is not essential for bacterial cellulose synthesis. Furthermore, investigating the signaling molecules that regulate phage-host interactions, we find that in a high cell density state (ΔluxO), bacterial cells upregulate their susceptibility to phage BX-1, which leads to a rapid development of resistance. Conversely, cells in a low-density state (ΔhapR) exhibit reduced susceptibility to phage BX-1 while still producing comparable phage progenies. This population density-dependent response is primarily enhanced by the predicted quorum-sensing autoinducer CAI-1, synthesized by the gene cqsA. Collectively, our findings reveal the intricate dynamics of phage-host interactions, adding a new layer of complexity to our understanding of phage receptor regulations.IMPORTANCEPhage therapy has garnered significant attention as a promising solution to antibiotic resistance in aquaculture. However, its application is hindered by a limited understanding of the genotypic and phenotypic dynamics governing phage-host interactions. Bacteria have developed various defense mechanisms against phages, such as mutations in phage receptors. In this study, we demonstrate that the bacterial cellulose biosynthesis-related gene bcsE plays a crucial role in determining susceptibility to phage BX-1, while quorum-sensing (QS) systems significantly influence collective phage-related behaviors. By characterizing the mechanisms of phage resistance and the regulatory role of QS in susceptibility, our findings enhance the understanding of phage-host interactions and pave the way for more effective phage therapy applications. Collectively, these insights illuminate the evolutionary complexities of phage-defense systems and the broader strategies that bacteria employ to coexist with phages.

Enhancing Treatment Decisions for Advanced Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutations: A Reinforcement Learning Approach.

Although higher-generation TKIs are associated with improved progression-free survival in advanced NSCLC patients with EGFR mutations, the optimal selection of TKI treatment remains uncertain. To address this gap, we developed a web application powered by a reinforcement learning (RL) algorithm to assist in guiding initial TKI treatment decisions. Clinical and mutational data from advanced NSCLC patients were retrospectively collected from 14 medical centers. Only patients with complete data and sufficient follow-up were included. Multiple supervised machine learning models were tested, with the Extra Trees Classifier (ETC) identified as the most effective for predicting progression-free survival. Feature importance scores were calculated by the ETC, and features were then integrated into a Deep Q-Network (DQN) RL algorithm. The RL model was designed to select optimal TKI generation and a treatment line for each patient and was embedded into an open-source web application for experimental clinical use. In total, 318 cases of EGFR-mutant advanced NSCLC were analyzed, with a median patient age of 63. A total of 52.2% of patients were female, and 83.3% had ECOG scores of 0 or 1. The top three most influential features identified were neutrophil-to-lymphocyte ratio (log-transformed), age (log-transformed), and the treatment line of TKI administration, as tested by the ETC algorithm, with an area under curve (AUC) value of 0.73, whereas the DQN RL algorithm achieved a higher AUC value of 0.80, assigning distinct Q-values across four TKI treatment categories. This supports the decision-making process in the web-based 'EGFR Mutant NSCLC Treatment Advisory System', where clinicians can input patient-specific data to receive tailored recommendations. The RL-based web application shows promise in assisting TKI treatment selection for EGFR-mutant advanced NSCLC patients, underscoring the potential for reinforcement learning to enhance decision-making in oncology care.

Osimertinib induced cardiac failure and atrial flutter in a patient with advanced pulmonary adenocarcinoma: A case report and review of the literature

&lt;b&gt;Background: &lt;/b&gt;Osimertinib-induced cardiotoxicity is a significant but rare condition. This article reports a case of an elderly patient who developed cardiac failure and atrial flutter due to Osimertinib treatment, potentially related to both the drug and the patient’s underlying factors.&lt;br /&gt; &lt;b&gt;Case presentation:&lt;/b&gt; A 63-year-old man diagnosed with advanced non-small cell lung cancer (NSCLC) with bone metastasis was found to have an epidermal growth factor receptor mutation (exon 19 deletion). He had undergone four prior treatment regimens, including afatinib and bevacizumab. After two years, he developed resistance and experienced brain and bone metastases, prompting a switch to Osimertinib (80 mg/day). Before starting Osimertinib, he had a history of coronary artery disease and hypertension, with a normal electrocardiogram (ECG) and a left ventricular ejection fraction (LVEF) of 53%. However, nearly two months after initiating Osimertinib, he was presented with cardiac failure symptoms, with LVEF decreasing to &amp;lt;53% and atrial flutter observed on ECG. Suspecting drug-induced cardiotoxicity, Osimertinib was discontinued. Following cessation of the drug, his cardiac function improved, and the ECG abnormalities resolved. This case represents the first reported instance of concurrent cardiac failure and atrial flutter associated with Osimertinib treatment.&lt;br /&gt; &lt;b&gt;Conclusions: &lt;/b&gt;As Osimertinib continues to significantly enhance survival in NSCLC, there remains a need for active monitoring of cardiac adverse events in patients undergoing Osimertinib treatment. These events can be life-threatening but are usually reversible after discontinuation of the drug.

Effects of EGFR-TKIs combined with intracranial radiotherapy in EGFR-mutant non-small cell lung cancer patients with brain metastases: a retrospective multi-institutional analysis

BackgroundPatients with non-small cell lung cancer (NSCLC) are prone to developing brain metastases (BMs), particularly those with epidermal growth factor receptor (EGFR) mutations. In clinical practice, treatment-naïve EGFR-mutant NSCLC patients with asymptomatic BMs tend to choose EGFR-tyrosine kinase inhibitors (TKIs) as first-line therapy and defer intracranial radiotherapy (RT). However, the effectiveness of upfront intracranial RT remains unclear.MethodsThis was a retrospective study including 217 patients from two institutions between January 2018 and December 2022. Clinical data of NSCLC patients with BMs who received EGFR-TKIs were collected. The patients were assigned to one of the three groups according to the therapeutic modality used: the upfront TKI + stereotactic radiosurgery (SRS) / fractionated stereotactic radiotherapy (fSRS) group (upfront TKI + SRS/fSRS ), the upfront TKI + whole-brain radiotherapy (WBRT) group (upfront TKI + WBRT) and the upfront TKI group.ResultsAs of March 8, 2023, the median follow-up duration was 37.3 months (95% CI, 32.5–42.1). The median overall survival (OS) for the upfront TKI + SRS/fSRS, upfront TKI + WBRT, and upfront TKI groups were 37.8, 20.7, and 24.1 months, respectively (p = 0.015). In subgroup analysis, the upfront TKI + SRS/fSRS group demonstrated longer OS compared to the upfront TKI + WBRT and upfront TKI groups in patients treated with first or second-generation EGFR-TKIs (p = 0.021) and patients with L858R mutation (p = 0.017), whereas no survival benefit was observed in three-generation EGFR-TKIs or 19del subgroup. In the multivariable analysis, metachronous BMs, EGFR L858R mutation and nonclassic EGFR mutation were identified as independent risk factors for OS, while a DS-GPA score of 2.0–4.0 was the only independent protective factor.ConclusionsThis study demonstrated that upfront addition of SRS/fSRS to EGFR-TKIs was associated with longer OS compared to upfront WBRT or upfront TKI alone in EGFR-mutant NSCLC patients with BMs. This improvement was more significant in patients with L858R mutation and those treated with first or second-generation EGFR-TKIs. Further research with a larger sample size is warranted.

Chrysin: A Potential Antiandrogen Ligand to Mutated Androgen Receptors in Prostate Cancer.

Androgen receptor mutations, particularly T877A and W741L, promote prostate cancer (PCa). The main therapies against PCa use androgen receptor (AR) antagonists, including Bicalutamide; but these drugs lose their effectiveness over time. Chrysin is a flavonoid with several biological activities, including antitumoral properties; however, its potential as an antiandrogen must be explored. The present study aimed to characterize and compare the molecular interactions of chrysin with wild-type and mutated ARs and their cytotoxic effect in an in vitro model of PCa. The affinities and molecular interactions of Bicalutamide and chrysin for the wild-type and mutated forms of AR were assessed by molecular docking. The MTT assay was used to evaluate the cytotoxic effect of these ligands on the DU-145 (T877A) and PC3 (W741L) PCa cell lines and on non-tumoral RWPE-1 cells. The molecular dockings predicted a higher affinity of chrysin for the mutated AR than the wild-type AR (WT-AR); meanwhile, Bicalutamide presented a higher affinity for WT-AR. The amino acid residues involved in molecular interactions within the binding site of these receptors changed according to the ligands and AR variants, affecting their affinity scores and biological effects (agonist/antagonists). Chrysin exerted a specific cytotoxic effect against the PCa tumoral cells but none against the non-tumoral cells. In contrast, Bicalutamide showed potent cytotoxicity against all cell lines. This study evidences the potential antiandrogen effect of chrysin on mutated AR and specific cytotoxicity against PCa cells, suggesting that this flavonoid could be considered for PCa therapy.

Hypoxia-inducible factor 1α is required to establish the larval glycolytic program in Drosophila melanogaster.

Objectives: The rapid growth that occurs during Drosophila larval development requires a dramatic rewiring of central carbon metabolism to support biosynthesis. Larvae achieve this metabolic state, in part, by coordinately up-regulating the expression of genes involved in carbohydrate metabolism. The resulting metabolic program exhibits hallmark characteristics of aerobic glycolysis and establishes a physiological state that supports growth. To date, the only factor known to activate the larval glycolytic program is the Drosophila Estrogen-Related Receptor (dERR). However, dERR is dynamically regulated during the onset of this metabolic switch, indicating that other factors must be involved. Here we examine the possibility the Drosophila ortholog of Hypoxia inducible factor 1α (Hif1α) is also required to activate the larval glycolytic program. Methods: CRISPR/Cas9 was used to generate new loss-of-function alleles in the Drosophila gene similar ( sima ), which encodes the sole fly ortholog of Hif1α. The resulting mutant strains were analyzed using a combination of metabolomics and RNAseq for defects in carbohydrate metabolism. Results: Our studies reveal that sima mutants fail to activate aerobic glycolysis and die during larval development with metabolic phenotypes that mimic those displayed by dERR mutants. Moreover, we demonstrate that dERR and Sima/Hif1α protein accumulation is mutually dependent, as loss of either transcription factor results in decreased abundance the other protein. Conclusions: These findings demonstrate that Sima/HIF1α is required during embryogenesis to coordinately up-regulate carbohydrate metabolism in preparation for larval growth. Notably, our study also reveals that the Sima-dependent gene expression profile shares considerable overlap with that observed in dERR mutant, suggesting that Sima/HIF1α and dERR cooperatively regulate embryonic and larval glycolytic gene expression. The Drosophila melanogaster gene similar ( sima ), which encodes the sole fly ortholog of Hif1α, is required to up-regulate glycolysis in preparation for larval growth. sima mutant larvae exhibit severe defects in carbohydrate metabolism and die during the second larval instar. sima mutant larvae exhibit the same metabolic phenotypes as Drosophila Estrogen Related Receptor ( dERR ) mutants, suggesting that these two transcription factors coordinately regulate the larval glycolytic program. Sima/Hif1α and dERR accumulation is mutually dependent, as loss of either transcription factor results in decreased abundance of the other.

Comparative analysis of EGFR mutations in circulating tumor DNA and primary tumor tissues from lung cancer patients using BEAMing PCR

In this study, we measured human epidermal growth factor receptor (EGFR) mutations in both tissue and circulating tumor DNA (ctDNA) by using beads, emulsions, amplifications and magnetic polymerase chain reaction (BEAMing PCR). Noninvasive mutation detection by assessing circulating tumor DNA (ctDNA) offers many advantages over tumor biopsy. One hundred non-small cell lung cancer (NSCLC) patients were enrolled, and both preoperative plasma samples and formalin-fixed and paraffin-embedded (FFPE) samples were collected for the study. The EGFR mutation status was determined by BEAMing PCR in ctDNA. Real-time quantitative PCR (qPCR) data were collected from our hospital database (EMR-qPCR, Electronic Medical Records) for comparative analysis. Additionally, qPCR was also performed on FFPE tissues using a Diatech EGFR qPCR kit. The concordance rates were 98.8%, 98.9% and 95.5% for exons 19, 20 and 21, respectively, when the BEAMing data were compared with the EMR-qPCR data. Additionally, when the BEAMing and Diatech qPCR data were compared, 90%, 100%, 96% and 98% of the genes were obtained for exons 19, 20, 21 (L858R) and 21 (L861Q), respectively. For both comparisons, Cohen’s kappa agreement was significant. The advantage of BEAMing is its ability to identify mutated DNA sequences in cancer cells in the background of normal cell DNA contamination. This could be useful for disease monitoring and progression.