Search Results (4,588)

Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in methylthioadenosine phosphorylase-deleted (MTAP-null) cancers. Second-generation methylthioadenosine (MTA)-cooperative PRMT5 inhibitors preferentially target MTAP-null cells while largely sparing MTAP-wildtype (MTAP-WT) cells, thereby improving tumor selectivity over first-generation PRMT5 inhibitors. Despite encouraging efficacy and safety signals in early clinical studies, the modest objective response rates (ORRs) observed with these inhibitors suggest that intrinsic or acquired resistance may limit their clinical benefit. Here, we investigated acquired resistance to the MTA-cooperative PRMT5 inhibitor BMS-986504/MRTX1719 in MTAP-null non-small cell lung cancer (NSCLC) cells and sought to identify therapeutic vulnerabilities that emerge upon resistance. Using multiple in vitro-derived resistant models, we found that acquired resistance was accompanied by cross-resistance to mechanistically distinct PRMT5 inhibitors. Notably, this phenotype was not fully explained by altered PRMT5 activity or changes in MTA levels. High-throughput drug screening of paired sensitive and resistant cells revealed increased sensitivity to MEK inhibitors following acquisition of MRTX1719 resistance in KRAS-wildtype NSCLC cells. Consistently, resistant cells exhibited rewired MAPK-related transcriptional programs. Together, these findings identify MEK inhibition as a reproducible collateral vulnerability associated with acquired MRTX1719 resistance in MTAP-null NSCLC models and support further evaluation of MEK inhibition as a potential treatment-switching strategy following resistance. Full article

Brain metastases represent a major clinical challenge in the management of non-small-cell lung cancer, particularly in patients with epidermal growth factor receptor mutations, constituting a leading cause of morbidity and mortality. In recent years, significant advancements have been made in both local therapies and systemic treatments. Nevertheless, managing central nervous system disease remains complex, encompassing challenges such as optimal therapy sequencing, resistance mechanisms, oligoprogression, the role of the blood–brain barrier, diagnostic strategies, and the influence of the brain tumor microenvironment. Despite advances, brain metastases in non-small-cell lung cancer remain an unmet need. Local treatments like radiotherapy are effective but carry risks of long-term neurological side effects, while the number and burden of brain metastases remain key prognostic factors. Surgical resection may be considered even in patients with multiple brain metastases to improve clinical status, enable further therapy, and enhance survival and quality of life. With the extension of survival afforded by systemic therapies, optimizing the balance between treatment efficacy and quality of life has become critical. Integrating patient perspectives is essential in navigating these complex clinical decisions. Full article

Background: Lung adenocarcinoma (LUAD) is the most prevalent histologic subtype of non-small cell lung cancer (NSCLC) and exhibits considerable molecular heterogeneity. Among the most clinically significant driver alterations are mutations in EGFR and KRAS, both of which influence treatment selection and oncologic outcomes. The prevalence of these mutations varies by race, yet racial minority populations remain underrepresented in genomic studies. EGFR alterations are more frequently observed in Asian patients, while KRAS mutations predominate in non-Asian cohorts. This study aimed to characterize race-associated differences in driver mutation prevalence among Asian, Black, and White patients with LUAD. Methods: A retrospective secondary cohort analysis was performed using publicly available clinicogenomic data from the Lung Adenocarcinoma Met Organotropism cohort, accessed via cBioPortal, comprising 2653 tumor samples. Patients were stratified by self-reported race into Asian, Black, and White cohorts; cases with missing race data were denoted as either other or unknown. Mutation frequencies for EGFR, KRAS, and TP53 were extracted from OncoPrint cohort study views and compared descriptively across groups. Results: Distinct race-associated differences in driver mutation prevalence were observed. Asian patients exhibited the highest frequency of EGFR alterations (64%), compared with Black (41%) and White (28%) cohorts. In contrast, KRAS mutations were least prevalent in Asian patients (10%) and more frequent in White (33%) and Black (23%) cohorts, indicating an inverse distribution between Asian and non-Asian populations. TP53 mutation prevalence was similar in Asian (52%) and White (53%) cohorts but was notably higher in Black patients (65%). Conclusions: Asian patients with LUAD exhibit a distinct molecular profile characterized by EGFR predominance, with direct implications for eligibility for EGFR-targeted tyrosine kinase inhibitor therapy. Black patients may also benefit from EGFR-based targeted therapies, but lack of large genomic data on Black populations warrants further investigation. White cohorts display a KRAS-dominant mutation pattern, suggesting divergent tumorigenic pathways and the potential need for alternative therapeutic strategies. The elevated TP53 frequency in Black patients remains to be further characterized. These findings support integrating race-associated genomic profiling into precision oncology frameworks to improve treatment selection and reduce disparities in outcomes. Full article

Background: We assessed the prognostic value of the pan-immune–inflammation value (PIV), systemic immune–inflammation index (SII), lung immune prognostic index (LIPI), and c-reactive protein–albumin–lymphocyte (CALLY) index in advanced non-small cell lung cancer (NSCLC) treated with first-line immune checkpoint inhibitor (ICI)-based therapy. Methods: This multicenter retrospective study included 161 patients who received ICI monotherapy, chemoimmunotherapy, or dual ICI therapy. The objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression models. Results: A high CALLY index was associated with a significantly higher CBR (82.1% vs. 59.5%; p = 0.015), longer PFS (14.95 vs. 7.13 months; p = 0.002), and longer OS (25.79 vs. 13.24 months; p = 0.003). In the multivariable analyses, a high CALLY index remained independently associated with improved PFS (HR = 0.52, p = 0.006) and OS (HR = 0.53, p = 0.010), whereas a high SII was independently associated with poorer PFS (HR = 1.74, p = 0.021) and OS (HR = 1.90, p = 0.009). PIV and LIPI were not independently associated with survival outcomes. Conclusions: SII and the CALLY index emerged as independent prognostic biomarkers in advanced NSCLC receiving first-line immunotherapy-based treatment. The CALLY index showed the strongest and most consistent association with clinical benefit, PFS, and OS. Full article

Laser-driven accelerated particle beams have significantly advanced cancer treatment by facilitating the delivery of exceptionally high dose rates of radiation to solid tumors within femto- to picosecond timescales. This investigation compared the radiobiological effectiveness of ultrashort pulsed electron beams, generated by the Advanced Research Electron Accelerator Laboratory (AREAL) accelerator, with conventional X-rays on two non-small cell lung cancer (NSCLC) cell lines: A549 (wild-type p53) and H1299 (p53-deficient). NSCLC cells were irradiated using either the AREAL accelerator (with a peak dose rate of 1.6 × 10¹⁰ Gy/s, a pulse duration of 4.5 × 10⁻¹³ s, and a repetition rate of 20 Hz) or an X-ray unit at an absorbed dose rate of 0.85 Gy/min. Clonogenic survival analysis, γH2AX foci enumeration, and genome-wide transcriptome analysis were conducted. Clonogenic survival curves showed increased radiosensitivity of A549 cells following AREAL exposure compared to X-rays (RBE = 1.2), whereas H1299 radiosensitivity remained unchanged. In both cell lines, AREAL exposure resulted in a greater dose-dependent accumulation of residual γH2AX foci 24 h after irradiation than conventional X-rays, suggesting more persistent DNA damage signaling. Transcriptomic analyses revealed broader gene expression changes after AREAL irradiation and suggested distinct p53-related responses. Pathway-level analysis demonstrated that A549 cells exhibited reduced DNA repair activity, accompanied by dysregulation of cell cycle progression and apoptosis, whereas H1299 cells displayed transcriptomic signatures consistent with enhanced homologous recombination activity. Overall, these findings indicate that ultrashort pulsed electron beams induce p53-related responses distinct from those of conventional X-rays and warrant further investigation of this technology as a potential radiotherapy modality. Full article

Background/Objectives: Loss of phosphatase and tensin homolog (PTEN) activity is a frequent feature of non-small-cell lung cancer (NSCLC), and epigenetic repression may contribute to its reduced expression. This study investigated the effects of 5-aza-2′-deoxycytidine (5-aza-dC) on PTEN, DNA methyltransferase 1 (DNMT1), PTEN promoter methylation-specific amplification patterns, and miR-148a-3p expression in NSCLC models. Methods: Publicly available cancer-genomics datasets were analyzed to compare PTEN and DNMT1 transcript abundance and to assess the association between PTEN methylation and transcript abundance in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). A549 and H460 cells were exposed to 2.5 or 5 µM 5-aza-dC for 72 h. Reverse-transcription quantitative PCR (RT-qPCR), Western blotting, methylation-specific PCR (MSP-PCR), and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were used to evaluate RNA expression, protein abundance, methylation-specific amplification, and metabolic activity, respectively. Results: Bioinformatic analyses showed lower PTEN and higher DNMT1 expression in both NSCLC subtypes, together with inverse associations between PTEN methylation and transcript abundance. In both cell lines, 5-aza-dC reduced MTT metabolic activity and DNMT1 expression. PTEN mRNA and protein abundance increased significantly at 5 µM, whereas no significant changes were detected at 2.5 µM. MSP-PCR revealed persistent heterogeneous PTEN methylation-specific amplification patterns without clear evidence of progressive promoter demethylation. miR-148a-3p exhibited a biphasic response in A549 cells but remained unchanged in H460 cells. Conclusions: These findings support an association between 5-aza-dC exposure, increased PTEN expression, and reduced DNMT1 expression in NSCLC cells. Quantitative methylation analysis and mechanistic validation are required to clarify the contribution of miR-148a-3p to this regulatory association. Full article

Early cancer detection is critical for improving patient outcomes, yet current diagnostic approaches often fail to identify malignancies when tumor-specific biomarkers are relatively scarce. Emerging CRISPR/Cas-based technologies have revolutionized the ultra-sensitive detection of cancer biomarkers in liquid biopsies, overcoming the inherent limitations of traditional diagnostic approaches such as tissue biopsies and imaging, which frequently fail to detect early-stage malignancies with sufficient sensitivity. This review explores recent advances in CRISPR/Cas diagnostics (CRISPR/Cas-Dx) that employ programmable CRISPR effectors, including Cas9, Cas12, Cas13, and Cas14. In particular, the collateral (trans-) cleavage activities of Cas12, Cas13, and Cas14 enable signal amplification for highly sensitive detection of circulating tumor DNA, microRNAs, exosomes, and other multi-omics biomarkers, often without the need for extensive nucleic acid amplification. Representative CRISPR/Cas-Dx platforms include amplification-coupled assays, amplification-free frameworks, biosensing and multiplexing capabilities, and new digital or droplet-based configurations that include artificial intelligence to improve analytical precision. These technologies demonstrate single-molecule resolution and adaptability for point-of-care testing in malignancies such as non-small cell lung, colorectal, and breast carcinoma. Finally, we outline a clinical translation roadmap encompassing manufacturability, regulatory and standardization requirements, and real-world implementation challenges. This perspective offers a blueprint for CRISPR-powered, ultra-sensitive liquid biopsy diagnostics that can enable population-scale early cancer screening and truly preventive oncology by bridging molecular insights, engineering innovation, and clinical imperatives. Full article

Approximately 30% of tumors contain an activating mutation in the oncogene KRAS, leading to increased cell proliferation that often promotes non-small cell lung cancers, colorectal adenocarcinomas, pancreatic ductal adenocarcinomas (PDAC), and other cancers. Among the most common point mutations in KRAS is G12D, an example of an oncogenic sequence present in tumor cells but not normal cells. We developed peptide nucleic acid (PNA) oligomers that selectively bind KRAS G12D sequences and fused them with novel cell-penetrating peptide flanking regions (CPP-PNA-G12D) then evaluated them. Electrophoretic mobility shift assays demonstrated in vitro binding to and selectivity for KRAS G12D over wild-type KRAS and KRAS G12C. Cells and nuclei were able to uptake CPP-PNA-G12D at high efficiency as shown by fluorescent microscopy and flow cytometry. Cell viability assays showed a striking dose-response effect in on-target cells expressing KRAS G12D, while relatively sparing off-target cells expressing KRAS G12C. CPP-PNA-G12D constructs were effective against a panel of PDAC cell lines and in female Balb/c mice bearing patient-derived xenografts. These results show promise for an enhanced PNA-delivery peptide conjugate strategy as a potential therapeutic strategy to selectively target KRAS mutant cancer cells, with the potential to expand this technology to additional cancer-derived mutant oncogenes. Full article

Locally advanced non-small cell lung cancer (NSCLC) is a biologically and clinically heterogeneous disease in which mediastinal lymph node involvement remains the principal prognostic and therapeutic discriminator. Accurate nodal staging guides selection among surgical resection, definitive chemoradiotherapy, immunotherapy, and targeted therapy. This narrative review synthesizes contemporary evidence on mediastinal staging modalities, nodal disease burden, and treatment selection in stage II-III NSCLC. Contemporary staging integrates CT and FDG-PET/CT with systematic tissue confirmation using EBUS-TBNA and EUS, with surgical mediastinal staging reserved for selected high-risk or discordant cases. The ninth edition TNM N2a/N2b distinction, increasing use of neoadjuvant and perioperative immunotherapy, and molecularly guided therapy have further amplified the clinical consequences of under- or over-staging. Nodal assessment should therefore be interpreted through a multidisciplinary framework that integrates anatomy, biology, treatment response, and patient operability. Full article

Lung cancer remains a leading cause of cancer-related mortality worldwide, underscoring the need for safer and more effective therapeutic strategies. In this study, zinc oxide nanoparticles (ZnO NPs) were synthesized via a green, biogenic approach using Lantana camara L. flower aqueous extract and evaluated for their anticancer potential against human non-small cell lung cancer (NSCLC) NCI-H460 cells. The biosynthesized ZnO NPs were characterized using UV-visible spectroscopy, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), Transmission electron microscopy (TEM), energy-dispersive X-ray analysis (EDX), X-ray diffraction (XRD) and particle size analysis, confirming the formation of nanocrystalline ZnO. LC-MS profiling of the Lantana camara flower extract revealed the presence of several bioactive phytochemicals, including phenolic compounds, terpenoids, fatty acids, and alkaloids, which may contribute to the reduction and stabilization of ZnO NPs during green synthesis. Cytotoxicity assessment of ZnO NPs using MTT and trypan blue exclusion assays revealed a dose-dependent reduction in cell viability, with an IC₅₀ value of 50 µg/mL. Mechanistic investigations demonstrated that ZnO NP exposure induced significant oxidative stress, evidenced by increased nitric oxide, lipid peroxidation, and reactive oxygen species levels, along with depletion of intracellular glutathione. Apoptotic cell death was further confirmed by nuclear DNA fragmentation, mitochondrial membrane depolarization, and G0/G1 phase cell cycle arrest. Quantitative real-time PCR analysis revealed upregulation of the pro-apoptotic genes Bax and p53, accompanied by downregulation of the anti-apoptotic gene Bcl-2, indicating activation of a mitochondrial-dependent intrinsic apoptotic pathway. Collectively, these findings suggest that Lantana camara L. flower-mediated ZnO nanoparticles induced apoptotic responses associated with oxidative stress in NSCLC cells, highlighting their ability as an eco-friendly nanoplatform for further anticancer investigations. Full article

Background: Immunotherapy has improved outcomes in non-small cell lung cancer (NSCLC), but reliable predictive biomarkers remain limited. DNA damage response (DDR) gene mutations may enhance tumor immunogenicity and response to immune checkpoint inhibitors (ICIs), yet clinical findings remain inconsistent. We aimed to systematically evaluate the association between DDR gene mutations and ICI outcomes in NSCLC. Methods: PubMed and Embase were searched for eligible studies. Data on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were extracted and pooled using random-effects models. Subgroup analyses were performed by treatment regimen. Results: A total of 13 studies involving 5989 patients were included from 606 records. The pooled RR for ORR comparing DDR wild-type with DDR-mutated patients was 0.63 (95% CI: 0.49–0.82, p < 0.001), indicating higher ORR in the DDR-mutated group. DDR mutations were also associated with improved PFS (HR = 0.56, 95% CI: 0.43–0.74, p < 0.001) and OS (HR = 0.82, 95% CI: 0.68–0.98, p < 0.05). In subgroup analyses, benefits were more consistent with ICI monotherapy, including improved PFS (HR = 0.59, 95% CI: 0.44–0.79, p < 0.001) and ORR (RR = 0.60, 95% CI: 0.44–0.82, p = 0.001), while OS showed a nonsignificant trend. Evidence in the ICI-plus-chemotherapy subgroup remained inconclusive because of the limited number of available studies and substantial between-study heterogeneity. Conclusions: DDR gene mutations were associated with improved clinical outcomes in NSCLC patients treated with ICIs, particularly in the ICI monotherapy setting. Full article

Background: Second-line treatment selection in relapsed extensive-stage small-cell lung cancer (ES-SCLC) is commonly guided by the platinum-free interval, but the optimal approach for patients progressing 3–6 months after first-line platinum-based therapy remains uncertain. We compared platinum-containing doublet chemotherapy with single-agent chemotherapy in this clinically ambiguous subgroup. Methods: This multicenter retrospective real-world cohort study included patients with ES-SCLC or recurrent metastatic SCLC after prior limited-stage disease who received first-line platinum-based chemotherapy, achieved disease control, and progressed within a platinum-free interval of 90–180 days. Treatment allocation was at the discretion of the treating physician and was not randomized. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Because of the non-randomized design, the treatment effect was examined across multiple analytic approaches, including multivariable Cox regression, propensity score adjustment, and stabilized inverse probability of treatment weighting (IPTW). Results: Of 105 patients, 54 received single-agent chemotherapy and 51 received platinum-containing doublet therapy; 39 (37.1%) had received first-line atezolizumab. Baseline characteristics were imbalanced in favor of the doublet group, which had a longer platinum-free interval, fewer pleural metastases, and a higher rate of objective response to first-line therapy. ORR was higher with doublet therapy (31.4% vs. 11.1%, p = 0.016), as was DCR (62.7% vs. 33.3%, p = 0.003). Median PFS was 4.4 months (95% CI 3.4–5.8) with doublet therapy versus 3.1 months (95% CI 2.7–3.7) with single-agent chemotherapy (unadjusted HR 0.53, 95% CI 0.36–0.80; p = 0.002). Median OS was 6.5 months (95% CI 5.4–8.0) versus 5.4 months (95% CI 4.1–6.0), a difference that was not statistically significant (HR 0.68, 95% CI 0.46–1.01; p = 0.054). The PFS estimate favored doublet therapy in all sensitivity analyses but was attenuated with increasingly complete adjustment for treatment selection (multivariable HR 0.46, 95% CI 0.29–0.72; propensity-adjusted HR 0.58, 95% CI 0.38–0.88; IPTW HR 0.68, 95% CI 0.38–1.20, p = 0.184). No OS estimate reached statistical significance in any model. Grade ≥ 3 adverse events were similar between groups (66.7% vs. 64.8%, p = 0.842). Conclusions: In this non-randomized cohort of patients relapsing within a 90–180-day platinum-free interval, platinum-containing doublet chemotherapy was associated with higher response rates and longer PFS, without an increase in severe toxicity, but no overall survival benefit was demonstrated. Because baseline prognostic factors consistently favored the doublet group and the PFS advantage was attenuated after propensity-based adjustment, these findings should be regarded as hypothesis-generating. They are nonetheless consistent with randomized data showing improved PFS but not OS with platinum rechallenge, and support platinum-containing rechallenge as a reasonable option in carefully selected patients rather than as a demonstrated survival-prolonging strategy. Full article

Traditional inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have long been characterized as classical antiproliferative agents that induce G1 cell cycle arrest by blocking the phosphorylation of the retinoblastoma protein (Rb). However, recent studies in lung cancer have expanded this paradigm, revealing a functional transition from exclusive tumor suppression to the profound remodeling of the tumor microenvironment (TME) to enhance antitumor immunity. This review systematically outlines the genomic aberrations of the CDK4/6-Rb axis across lung cancer subtypes and dissects its immunomodulatory networks. These encompass the activation of effector T cells, the alleviation of immunosuppression mediated by regulatory T cells (Tregs), and the enhancement of antigen presentation via the Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Furthermore, we analyze acquired resistance mechanisms, primarily focusing on p21-CDK2 bypass activation mediated by Cyclin E1 gene (CCNE1) amplification and tumor protein 53 gene (TP53) mutations. We also review clinical investigations combining CDK4/6 inhibitors with targeted therapies against driver genes, as well as immune checkpoint inhibitors in lung cancer. Notably, in the context of lung cancer, these combinatorial strategies have been primarily investigated in the second-line or subsequent settings following progression on standard platinum-based chemotherapy or immunotherapy. Finally, we propose individualized, stratified treatment strategies based on genomic and immunological biomarkers, providing a translational framework for overcoming multidrug resistance and optimizing next-generation combinatorial regimens in lung cancer. Full article

Accurate segmentation of non-small cell lung cancer (NSCLC) on positron emission tomography/computed tomography (PET/CT) is an essential prerequisite for automated metabolic tumor volume (MTV) quantification and staging. Although deep learning models achieve high performance on large-scale datasets, their generalization across different clinical domains is limited by variations in imaging protocols and patient demographics. This study aims to evaluate several deep learning architectures and investigate a transfer learning strategy to mitigate domain shift. Three architectures, including ResNet-backbone 3D U-Net, nnU-Net v2, and Swin UNETR, were benchmarked from scratch and compared with a fine-tuned nnU-Net initialized with AutoPET II weights. Results on the internal dataset showed that the fine-tuned nnU-Net achieved a Dice similarity coefficient (DSC) of 83.4 ± 6.5%, a 95% Hausdorff distance (HD95) of 5.1 ± 3.6 mm, and a precision of 89.6 ± 8.2%. Compared to the nnU-Net v2, the fine-tuned nnU-Net improved the absolute DSC by 6.8% while reducing local training time by 37.5% by bypassing the initial feature-learning phase. The fine-tuned nnU-Net model also demonstrated a high correlation between the MTV and the ground truth (Pearson r = 0.96, p < 0.001), indicating its potential as a reliable automated approach for quantitative MTV extraction and NSCLC prognostic-related analysis. Full article

Background/Objectives: Reliable preoperative assessment of treatment response after neoadjuvant chemoimmunotherapy in locally advanced non-small-cell lung cancer (NSCLC) remains challenging because conventional imaging may not accurately distinguish viable tumour from treatment-related fibrosis or immune-mediated changes. This study investigated whether CT-derived radiomic features combined with machine learning could improve the identification of patients achieving pathological complete response (pCR). Methods: Twenty-nine consecutive patients with stage III NSCLC who underwent surgical resection following neoadjuvant chemoimmunotherapy were retrospectively analysed. Radiomic features were extracted from preoperative CT scans and used to develop supervised machine-learning models based on Random Forest, Support Vector Machine, K-Nearest Neighbors, Multi-Layer Perceptron, and Logistic Regression algorithms. Histopathological findings after surgery served as the reference standard. Feature distributions were compared between patients with and without pCR using the Mann–Whitney U test with Bonferroni correction. Results: Surgical procedures included 19 lobectomies, 2 bilobectomies, 3 pneumonectomies, and 5 complex major resections. Pathological complete response was observed in 9 of 29 patients (31%). The proposed radiomics-based model achieved an area under the ROC curve of 0.92 (95% CI, 0.81–1.00), with 91% accuracy, 90% sensitivity, and 92% specificity (p < 0.05). All patients classified by the model as complete responders were confirmed to have pathological complete response at postoperative histological examination. Conclusions: CT-based radiomics combined with machine learning demonstrated promising performance for the preoperative prediction of pathological response after neoadjuvant chemoimmunotherapy in stage III NSCLC. Although these findings require external validation in larger prospective cohorts, this approach may support preoperative treatment assessment and surgical decision-making. Full article