Therapy For Non-small Cell Lung Cancer Research Articles

Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer

The fusion event between EML4 and ALK drives a significant oncogenic activity in 5% of non-small cell lung cancer (NSCLC). Even though potent ALK-tyrosine kinase inhibitors (ALK-TKIs) are successfully used for the treatment of EML4-ALK-positive NSCLC patients, a subset of those patients eventually acquire resistance during their therapy. Here, we investigate the kinase responses in EML4-ALK V1 and V3-harbouring NSCLC cancer cells after acute inhibition with ALK TKI, lorlatinib (LOR). Using phosphopeptide chip array and upstream kinase prediction analysis, we identified a group of phosphorylated tyrosine peptides including ERBB and AKT proteins that are upregulated upon ALK-TKI treatment in EML4-ALK-positive NSCLC cell lines. Dual inhibition of ALK and ERBB receptors or AKT disrupts RAS/MAPK and AKT/PI3K signalling pathways, and enhances apoptosis in EML4-ALK + NSCLC cancer cells. Heregulin, an ERBB3 ligand, differentially modulates the sensitivity of EML4-ALK cell lines to ALK inhibitors. We found that EML4-ALK cells made resistant to LOR are sensitive to inhibition of ERBB and AKT. These findings emphasize the important roles of AKT and ERBB3 to regulate signalling after acute LOR treatment, identifying them as potential targets that may be beneficial to prevent adaptive resistance to EML4-ALK-targeted therapies in NSCLC.

Ampelopsis japonica enhances the effect of radiotherapy in non-small cell lung cancer.

Radiotherapy is widely used in the clinical treatment of non-small cell lung cancer (NSCLC); however, its effectiveness often proves unsatisfactory. Ampelopsis japonica (AJ) is atraditional Chinese herb with anti-inflammatory and anticancer activities. However, whether AJ could enhance the effect of radiotherapy in NSCLC needs to be further explored. In vivo, BALB/c nude mice were used for axenograft tumor model to explore whether AJ could enhance the effect of radiation therapy (RT) in NSCLC. In vitro, human NSCLC cell lines HCC827 and H1299 were used to explore the effect of AJ on the cell proliferation and apoptosis of RT-treated NSCLC. Moreover, bioinformatic analysis was performed to analyze the signaling pathways regulated by AJ. Ampelopsis japonica enhanced the inhibitory effect of RT on NSCLC tumor growth in vivo. Simultaneously, AJ further enhanced the inhibitory effect of RT on NSCLC proliferation and the promoting effect of RT on NSCLC apoptosis. Bioinformatic analysis showed that AJ regulated the PI3K-Akt signaling pathway. We confirmed that AJ decreased the protein levels of the PI3K-Akt signaling pathway. Furthermore, the combination of AJ and RT suppressed activation of the PI3K-Akt signaling pathway. Ampelopsis japonica augmented the inhibitory impact of RT on NSCLC cell proliferation and tumor growth by suppressing the PI3K-Akt signaling pathway.

The anti-tumor effects of main component (benzethonium chloride) of butorphanol tartrate injection in non-small cell lung cancer

Cancer is one of the leading causes of morbidity and mortality in the global population. The effective management of cancer-associated pain and anesthesia are critical aspects of comprehensive cancer treatment. However, the role and mechanism of anesthesia and analgesia-related drugs in tumors remain controversial. In this study, the efficacy of 16 commonly used analgesics and anesthetics against non-small cell lung cancer (NSCLC) was evaluated. Among the 16 examined injections, butorphanol tartrate injection significantly inhibited the proliferation of NSCLC cells and increased the sensitivity of the EGFR-TKI-resistant H1975 cell line to gefitinib. Benzethonium chloride (BC) is the main active antitumor ingredient of butorphanol tartrate injection. BC may regulate the cell cycle, apoptosis and EMT signaling pathways by modulating the P53 signaling pathway. Our study reveals the therapeutic value of butorphanol tartrate injection and BC in the treatment of NSCLC and provides a theoretical basis for comprehensive therapies for NSCLC.

Explainable Machine Learning Predictions for the Benefit From Chemotherapy in Advanced Non-Small Cell Lung Cancer Without Available Targeted Mutations.

Non-small cell lung cancer (NSCLC) is a global health challenge. Chemotherapy remains the standard therapy for advanced NSCLC without mutations, but drug resistance often reduces effectiveness. Developing more effective methods to predict and monitor chemotherapy benefits early is crucial. We carried out a retrospective cohort study of NSCLC patients without targeted mutations who received chemotherapy at West China Hospital from 2009 to 2013. We identified variables associated with chemotherapy outcomes and built four predictive models by machine learning. Shapley additive explanations (SHAP) interpreted the best model's predictions. The Kaplan-Meier method assessed key variables' impact on 5-year overall survival. The study enrolled 461 NSCLC patients. Eight variables were selected for the model: differentiation, surgery history, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), total bilirubin (TBIL), total protein (TP), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH). The extreme gradient boosting (Xgboost) model exhibited superior discriminatory ability in predicting complete response (CR) probabilities to chemotherapy, with an AUC of 0.78. SHAP plots showed surgery history and high differentiation were related to CR benefits from chemotherapy. Absence of surgery, higher NLR, higher PLR, and higher LDH were all independent prognostic factors for poor survivals in NSCLC patients without mutations receiving chemotherapy. By machine learning, we developed a predictive model to assess chemotherapy benefits in NSCLC patients without targeted mutations, utilizing eight readily available and non-invasive clinical indicators. Demonstrating satisfactory predictive performance and clinical practicability, this model may help clinicians identify patients' tendency to benefit from chemotherapy, potentially improving their prognosis.

Study on the inhibition of non-small cell lung cancer mediated by chitosan-based gene carrier delivering STAT3-shRNA

Systemic chemotherapy and radiotherapy often yield poor effect in the postoperative treatment of non-small cell lung cancer (NSCLC) and induce drug resistance. Herein, we proposed a targeted therapeutic approach utilizing gene carrier-mediated specific shRNA method. Firstly, the targeted short hairpin shRNA sequence, designed based on the STAT3 gene sequence, was inserted into the eukaryotic expression vector pGPU6/GFP/Neo to form the recombinant plasmid STAT3-shRNA. Next, a novel gene carrier, Vitamin E Succinate-Chitosan-Histidine (VES-CTS-His, VCH), was synthesized through an acylation reaction. The VCH was combined with pGPU6/GFP/Neo STAT3-shRNA recombinant plasmid by electrostatic interactions to form stable particles. VCH/pDNA, with typical nanoscale dimensions, could accumulate in tumor tissues through the EPR effect and enter tumor cells via endocytosis. VCH exhibited good pH responsiveness and could dissociate in the acidic microenvironment of tumors, thereby releasing the plasmids. Subsequently, the plasmids could downregulate STAT3 expression through RNAi effect. Inhibiting or blocking the expression of the STAT3 gene could significantly enhance the apoptotic induction and growth inhibition effects on NSCLC cells through the PI3K and mTOR signaling pathways, thereby achieving the goal of tumor treatment. This study provides a novel method for the construction of novel non-viral gene carriers and clinical gene-targeted therapy for NSCLC.

Formulation and evaluation of cetuximab functionalized phospholipid modified nanocrystals of paclitaxel for non-small cell lung cancer therapy

Present work aims to prepare Soluplus stabilized, phospholipid-modified, and cetuximab-conjugated paclitaxel nanocrystals (NCs) as stable nanocarriers for targeted drug delivery. The NCs, prepared using concurrent antisolvent precipitation cum cold crystallization method followed by probe sonication, were found to be monodispersed particles with sub-200 nm size. The microscopic analysis uncovered rod and spherical anisotropy for Soluplus stabilized (PTX-NCs) and phospholipid modified (Lipid/PTX-NCs) nanocrystals, respectively. The formation of amorphous PTX-NCs and subsequent coating with phospholipid was confirmed by solid-state characterization using differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform Infrared Spectroscopy (FTIR). X-ray Photoelectron Spectroscopic (XPS) analysis, indicated successful conjugation of cetuximab on NCs surface. Lipid coating rendered a sustained drug release behaviour to NCs at physiological pH. In vitro cell line studies confirmed the improved cellular internalization and better apoptosis induction capability of NCs, consequently resulting in enhanced efficacy of PTX against A549 cancer cells. Moreover, in Benzo[a] pyrene-induced lung cancer model, Cmab/Lipid/PTX-NCs showed significant improvement in tumor inhibition potential in comparison to pure PTX. The prepared Cmab/Lipid/PTX-NCs also exhibited improved pharmacokinetics performance, avoided off-target distribution, and showed a reduction in systemic toxicity. The findings of this study indicate the promising potential of the prepared cetuximab-functionalized phospholipid-coated paclitaxel nanocrystals in lung cancer therapy.

β-carboline compound-10830733 suppresses the progression of non-small cell lung cancer by inhibiting the PI3K/Akt/GSK 3β signaling pathway

Lung cancer is one of the most commonly diagnosed cancers worldwide, with non-small cell lung cancer (NSCLC) accounting for 80–85% of cases. To clarify the mechanisms underlying its onset and development, and to identify small molecule compounds that target related pathways effectively inhibiting tumor development and transformation. Small molecular compounds with a β-carboline nucleus exhibit a range of biological activities, with significant anti-tumor effects. A series of small molecule β-carboline compounds were synthesized and the dominant structure 1- (3-chlorophenyl) - 9H -pyridino - [3,4-b] indole - 3 -carboxylic acid methyl ester (10830733) was initially screened out. However, the effect of 10830733 on NSCLC is unclear. In this study, we investigated the anti-NSCLC activity of 10830733 and explored its potential mechanisms of action. First, we found that 10830733 decreased proliferation and invasion and promoted apoptosis, as well as S and G2 phase cell cycle arrest in NSCLC cells. Furthermore, network pharmacological analysis and Western blot confirmed that 10830733 inhibits the PI3K/Akt/GSK 3β pathway, and that the PI3K inhibitor LY294002 enhances the effects of 10830733 on proliferation, invasion, apoptosis, S and G2 phase arrest, and the expression of PI3K/Akt/GSK 3β related proteins. In conclusion, our data demonstrate that 10830733 reduces proliferation and invasion, promotes S and G2 phase arrest and apoptotic cell death in NSCLC cells by suppressing the PI3K/Akt/GSK 3β signaling pathway, suggesting that 10830733 could be a promising new candidate for NSCLC therapy.

Abstract PR004: Age-induced chronic accumulation of glucocorticoids drives therapy resistance in lung cancer

Abstract Non-small cell lung cancer (NSCLC), a highly aggressive cancer, is the leading cause of cancer- related deaths in the U.S. While chemotherapy and targeted therapy are the main treatment modalities in the clinic, many patients do not respond to these treatments. Strikingly, the median age for lung cancer diagnosis is 71. Yet, preclinical and clinical research have largely been skewed towards young mice and patients. Here, we address this gap in knowledge and evaluate if old age affects the response to standard of care NSCLC therapies in KRAS-driven NSCLC. Using human sera from young and old healthy subjects to treat NSCLC cell lines, we show that age-driven circulatory changes are sufficient to drive a state of profound resistance to both chemotherapies as well as KRASG12C targeted therapies. We confirmed the relevance of our findings in vivo, by transplanting cancer cells derived from the K-rasLSL-G12D/+; p53fl/fl genetically engineered mouse model of lung cancer into young and old C57BL/6 mice. Using this model we showed that unlike young lung tumor-bearing mice on chemotherapy, old tumor-bearing mice do not respond to treatment and have a poor prognosis. Mechanistically, we found that old age drives a transcriptional reprogramming that favors drug resistance and identified the glucocorticoid receptor as a major driver of these transcriptional changes. We traced this to an age-induced chronic accumulation of glucocorticoids in circulation and within the tumor interstitial fluid. Chronic treatment with age-relevant concentrations of cortisol alone was sufficient to drive glucocorticoid receptor activation and induce resistance to therapies mirroring the effects of old age. Further supporting a driving role for glucocorticoids in driving age- induced drug resistance, blocking the glucocorticoid receptor genetically or pharmacologically rescues the drug resistance state imposed by old age in NSCLC cells. Lastly, using TCGA patient data we show an inverse correlation between glucocorticoid receptor activation (GR score) and progression-free survival of lung cancer patients. Together, our work demonstrates a role for age-induced glucocorticoids in circulation in promoting therapy-resistance in NSCLC patients and supports the use of therapeutic agents that block the glucocorticoid receptor as a strategy to increase therapy efficacy in NSCLC patients. Citation Format: Devesh Raizada, Felicia Lazure, Stanislav Drapela, Nadir Sarigul, Joanne Tejero, Didem Ilter, Ana Da Silva Gomes. Age-induced chronic accumulation of glucocorticoids drives therapy resistance in lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR004.

Utilizing the T cell immune response to treat non-small cell lung cancer with CRISPR/Cas9 technology

Abstract. Non-small cell lung cancer (NSCLC) has the greatest incidence rate and fatality, among all the lung cancer types. Its treatment has been widely concerned by the research community. Currently, many inhibitors used in clinical practice face drawbacks such as increased drug resistance in cancer cells and failure, as well as relatively high cytotoxicity. They not only fail to have a long-term effect on the lesion may also cause certain damage to normal cells. Therefore, finding a treatment method that cancer cells cannot or are difficult to develop drug resistance, can have long-lasting effects, and has low cytotoxicity is currently the research direction of scholars. CRISPR/Cas9 technology, a widely used and convenient gene editing method, can modify the microenvironment of T cells or cancer cells as a therapy of NSCLC. This article aims to review the current mechanisms of using CRISPR/Cas9 technology to treat NSCLC looking forward to more treatment sites and methods in the future.

Abstract B036: Pathway repression in progression on osimertinib therapy in NSCLC via a comprehensive genomic and epigenomic circulating tumor DNA (ctDNA) assay

Abstract Background: Osimertinib is currently the most common precision therapy for patients with non- small cell lung cancer (NSCLC) with EGFR mutations. While it prolongs progression-free survival, resistance eventually develops in many, leading to disease progression. Somatic NGS has identified resistance mutations in the EGFR pathway and other oncogenes, but these account for only 40-45% of cases, suggesting non-genetic factors, such as epigenetic changes, may be involved. This study investigates the epigenetic landscape at diagnosis and progression on first- line osimertinib, focusing on cases with and without canonical resistance mutations. Methods: We defined two cohorts from GuardantINFORM, a clinico-genomics database, restricting to only patients with a test on the Guardant Infinity platform, a comprehensive blood-based NGS assay, that analyzes DNA sequence variants and performs extensive methylation profiling (∼15Mb) in >20,000 differentially methylated regions (DMRs) assessed for sample-specific methylation patterns. (A) Diagnosis Cohort: Comprised of 34 NSCLC patients with blood samples collected within six days prior to the initiation of first-line osimertinib therapy. (B) Progression Cohort: Comprised of 36 patients who were on first-line osimertinib therapy, with blood samples collected within 60 days of discontinuation. The progression cohort was further stratified based on the presence or absence of known resistance mutations identified through somatic variant analysis by Guardant360. Gene set enrichment analysis was conducted on these methylation profiles using the Reactome database to define pathway-level differences between the cohorts. Results: Pathway enrichment analysis in the diagnosis and progression cohorts found expected biological processes in NSCLC such as extracellular matrix organization, G- protein coupled receptor (GPCR) signaling, and FGFR pathways. Additionally, the progression cohort lacking canonical resistance mutations (n=23) exhibited unique enrichment in two specific pathways: Glucose-dependent Insulinotropic Polypeptide and Physiological Factors. These pathways include genes such as GATA4, which has been implicated in the epithelial- mesenchymal transition (EMT)—a process associated with transforming to a small cell phenotype, a known mechanism of resistance to EGFR inhibition, including osimertinib. Conclusion: This study demonstrates the utility of epigenetic profiling via liquid biopsies in uncovering non-genetic mechanisms underlying osimertinib resistance in advanced NSCLC. Identification of unique epigenetic pathways in progressing patients without canonical resistance mutations highlights the potential for discovering novel biomarkers of resistance. Further investigation into these findings may advance our understanding of resistance mechanisms across various cancer therapies, particularly for patients without identified genomic resistance, and inform clinical decision-making and trial design. Citation Format: Aaron Hardin, Leslie Bucheit, Amar Das, Craig Eagel, Helmy Eltoukhy. Pathway repression in progression on osimertinib therapy in NSCLC via a comprehensive genomic and epigenomic circulating tumor DNA (ctDNA) assay [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B036.

Bioorthogonal Chemistry-Guided Inhalable Nanoprodrug to Circumvent Cisplatin Resistance in Orthotopic Nonsmall Cell Lung Cancer.

Pulmonary delivery of anticancer therapeutics has shown encouraging performance in treating nonsmall cell lung cancer (NSCLC), which is characterized by high aggressiveness and poor prognosis. Cisplatin, a key member of the family of DNA alkylating agents, is extensively employed during NSCLC therapy. However, the development of chemoresistance and the occurrence of side effects severely impede the long-term application of cisplatin-based chemotherapies. Herein, we propose a meaningful strategy to precisely treat cisplatin-resistant NSCLC based on the combination of bioorthogonal chemistry with an inhalation approach. Ethacraplatin (EA-Pt), a platinum prodrug (IV), was synthesized and encapsulated in nitric oxide (NO)-containing micelles to overcome cisplatin chemoresistance. By further modifying bioorthogonal molecules in this nanoplatform (EA-Pt@MDBCO), an improved targeting performance toward pulmonary cancerous regions is achieved after prelabeling with azide via inhalation. Upon entering acidic cancer cells, EA-Pt is swiftly released due to the pH sensitivity of bioorthogonal micelles, which enables its bifunctions to inhibit glutathione S-transferase activity and deplete intracellular glutathione, eventually reversing cisplatin resistance. Moreover, the released NO also improves the overall therapeutic outcome against NSCLC. Consequently, inhalable EA-Pt@MDBCO prelabeled by azide effectively inhibits the progression of cisplatin-resistant orthotopic NSCLC, offering a feasible nanostrategy to expand the treatment options for NSCLC.

An integrated bioinformatics approach to early diagnosis, prognosis and therapeutics of non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) is one of the most deadly tumors characterized by poor survival rates. Advances in therapeutics and precise identification of biomarkers can potentially reduce the mortality rate. Thus, this study aimed to identify a set of common and stable gene biomarkers through integrated bioinformatics approaches that might be effective for NSCLC early diagnosis, prognosis, and therapies. Four gene expression profiles (GSE19804, GSE19188, GSE10072, and GSE32863) downloaded from the Gene Expression Omnibus database to identify common differential expressed genes (DEGs). A total of 213 overlapping DEGs (oDEGs) between NSCLC and healthy samples were identified by using statistical LIMMA method. Then 6 common top-ranked key genes (KGs) (CENPF, CAV1, ASPM, CCNB2, PRC1, and KIAA0101) were selected by using four network-measurer methods in the protein– protein interaction network. The GO functional and KEGG pathway enrichment analysis were performed to reveal some significant functions and pathways associated with NSCLC progression. Transcriptional and post-transcriptional factors of KGs were identified through the regulatory interaction network. The prognostic power and expression level of KGs were validated by using the independent data through the Kaplan–Meier and Box plots, respectively. Finally, 4 KGs–guided repositioning candidate drugs (ZSTK474, GSK2126458, Masitinib, and Trametinib) were proposed. The stability of three top-ranked drug-target interactions (CAV1 vs. ZSTK474, CAV1 vs. GSK2126458, and ASPM vs. Trametinib) were investigated by computing their binding free energies for 140 ns MD-simulation based on MM-PBSA approach. Therefore, the findings of this computational study may be useful for early prognosis, diagnosis and therapies of NSCLC.

In vitro effectiveness of CB469, a MET tyrosine kinase inhibitor in MET-activated cancer cells

Gene alterations in receptor tyrosine kinases can result in oncogenic driver mutation in non-small cell lung cancer (NSCLC) including in genes like EGFR, ALK and MET. MET amplifications and MET exon14 skipping are the primary genetic changes in MET-altered cancers. Acquired MET mutations mediate resistance to clinical MET-targeted therapy in NSCLC. MET kinase domain secondary mutations (D1228X, Y1230X) confer resistance to type I MET tyrosine kinase inhibitors (TKIs) in METexon14-altered or MET amplified NSCLC. Here, we investigated the preclinical activity of a novel MET inhibitor, CB469, with cell growth, signaling pathway and colony formation. We confirmed that CB469 inhibited the activity of MET wild and secondary mutant kinases, D1228N and Y1230H, as a type II inhibitor. CB469 also inhibited cell growth and cell signaling proteins in MET-activated or MET exon14 skipping-mutated cancer cell lines and NIH/3T3 cells expressing an engineered MET mutant. CB469 exhibited the inhibitory efficacy comparable with that of capmatinib in migration of EBC-1(METwt) and Hs746T(METΔex14) cells. Finally, CB469 showed selective and potent inhibition in MET-activated cancer cells among MET TKIs leading to enhanced selectivity for MET-mutant versus wild type MET with inhibition of cell growth in NIH/3T3 cells expressing an engineered MET mutant variant.

Short-term treatment response assessment in non-surgical treatment of advanced non-small cell lung cancer based on radiomics of dual-energy CT

PurposeTo build and evaluate a pre-treatment dual-energy CT(DECT)-based clinical-radiomics nomogram for individualized prediction of short-term treatment response to non-surgical treatment in advanced non-small cell lung cancer (NSCLC). MethodsPre-treatment DECT images were retrospectively collected from 98 pathologically confirmed NSCLC with clinical stage III or IV. Short-term treatment response was determined with follow-up CT of 4–6 courses of treatment. Quantitative radiomics metrics of the lesion were extracted from dual-energy mixed images at venous phase. Least absolute shrinkage and selection operator and correlation analysis were used to select the most relevant radiomics features. Radiomics model, clinical model and clinical-radiomics model were established by multivariate logistic regression. The model with the best prediction performance was visualized as a nomogram, and the consistency between the probability of the actual occurrence of the outcome and the probability predicted by the model was measured by calibration curves. ResultsClinical stage, difference in electron density in arteriovenous phase, difference in slope of energy spectrum in arteriovenous phase, and slope of energy spectrum in venous phase of the tumor were significant clinical predictors of therapy response (P < 0.05). The clinical-radiomics model showed a higher predictive capability (AUC: 0.87 and 0.85 in training and validation sets, respectively) than the radiomics models and the clinical model. The clinical-radiomics nomogram integrating the DECT radiomics signature with clinical stage and spectrum parameters showed good calibration and discrimination. ConclusionThe clinical-radiomics nomogram based on pre-treatment DECT showed good performance in predicting clinical response to non-surgical therapy in NSCLC.

Real-World Evaluation of Treatment Patterns, Healthcare Costs, and Healthcare Resource Utilization Among Patients with Non-small Cell Lung Cancer in the US Receiving Sotorasib.

Sotorasib was the first drug approved for adults with Kirsten rat sarcoma G12C-mutated locally advanced/metastatic non-small cell lung cancer (NSCLC) who received prior systemic therapy in the US. This study aimed to provide initial real-world evidence on patient characteristics, treatment patterns, healthcare resource utilization (HCRU), and healthcare costs (HCC) associated with sotorasib in US clinical practice. A retrospective observational study was conducted using the Optum Clinformatics® Data Mart US claims database spanning January 2016 to March 2023. The study population included adults with a diagnosis of lung cancer (diagnosis (Dx) date), claims for sotorasib on/post-Dx date (index date), Continuous enrollment for medical/pharmacy benefits from 180 days pre-Dx date to≥30 days post-index date was required. Patients receiving treatments for small-cell lung cancer (SCLC) pre-index were excluded. Outcomes were analyzed for patients receiving sotorasib as second or subsequent line (2L+) treatment and included adherence [proportion of days covered (PDC)], treatment duration, time to next treatment (TTNT), HCRU, and HCC during sotorasib treatment. Among 169 patients with lung cancer that met all inclusion criteria, 140 patients received sotorasib as 2L+ treatment (mean age: 71 years; 67.1% females). Mean PDC for sotorasib was 94.9%. Kaplan-Meier median treatment duration was 4.3 months. Median TTNT in patients with subsequent treatment (n=31) was 6.8 months. During sotorasib treatment, patients had a mean 3.87 outpatient, 0.09 inpatient, and 0.11 emergency visits per month. Mean monthly HCC during sotorasib treatment were US$23,063 versus $25,541 during the 180-day pre-index period. Patients in the US receiving sotorasib as 2L+ therapy for NSCLC in real-world clinical practice showed high adherence, TTNT comparable to progression-free survival observed in clinical trials, and HCC similar to those immediately prior to treatment demonstrating real-world benefits with no additional impact on healthcare resources with sotorasib.

Deep learning analysis of histopathological images predicts immunotherapy prognosis and reveals tumour microenvironment features in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer mortality worldwide. Immune checkpoint inhibitors (ICIs) have emerged as a crucial treatment option for patients with advanced NSCLC. However, only a subset of patients experience clinical benefit from ICIs. Therefore, identifying biomarkers that can predict response to ICIs is imperative for optimising patient selection. Hematoxylin and eosin (H&E) images of NSCLC patients were obtained from the local cohort (n = 106) and The Cancer Genome Atlas (TCGA) (n = 899). We developed an ICI-related pathological prognostic signature (ir-PPS) based on H&E stained histopathology images to predict prognosis in NSCLC patients treated with ICIs using deep learning. To accomplish this, we employed a modified ResNet model (ResNet18-PG), a widely-used deep learning architecture well-known for its effectiveness in handling complex image recognition tasks. Our modifications include a progressive growing strategy to improve the stability of model training and the use of the AdamW optimiser, which enhances the optimisation process by adjusting the learning rate based on training dynamics. The deep learning model, ResNet18-PG, achieved an area under the receiver operating characteristic curve (AUC) of 0.918 and a recall of 0.995 on the local cohort. The ir-PPS effectively risk-stratified NSCLC patients. Patients in the low-risk group (n = 40) had significantly improved progression-free survival (PFS) after ICI treatment compared to those in the high-risk group (n = 66, log-rank P = 0.004, hazard ratio (HR) = 3.65, 95%CI: 1.75-7.60). The ir-PPS demonstrated good discriminatory power for predicting 6-month PFS (AUC = 0.750), 12-month PFS (AUC = 0.677), and 18-month PFS (AUC = 0.662). The low-risk group exhibited increased expression of immune checkpoint molecules, cytotoxicity-related genes, an elevated abundance of tumour-infiltrating lymphocytes, and enhanced activity in immune stimulatory pathways. The ir-PPS signature derived from H&E images using deep learning could predict ICIs prognosis in NSCLC patients. The ir-PPS provides a novel imaging biomarker that may help select optimal candidates for ICIs therapy in NSCLC.

Indolo[3,2-c]isoquinoline Hydroxamic Acid Derivatives as Novel Orally Topoisomerase-Histone Deacetylase Dual Inhibitors for NSCLC Therapy.

Based on the synergistic effects of topoisomerase (Top) inhibitors and histone deacetylase (HDAC) inhibitors in cancer therapy, a series of novel Top/HDAC dual inhibitors were designed and synthesized herein. The optimal compound 31 was identified to simultaneously inhibit both Tops and HDACs with potent antiproliferative activity against nonsmall cell lung cancer (NSCLC). Mechanistic studies indicated that compound 31 with increasing reactive oxygen species levels damages DNA, inhibiting cancer cell colony formation and migration and inducing both cancer cell apoptosis and cycle arrest. Noteworthily, compound 31 was orally active in the NSCLC xenograft model, and its antitumor efficacy (TGI = 77.5%, 100 mg/kg) was superior to that of HDAC inhibitor SAHA and SAHA in combination with the Top inhibitor irinotecan. Consequently, this work highlights the therapeutic potential of compound 31 as the Top/HDAC dual inhibitor in NSCLC therapy and provides valuable lead compounds for the further development of antitumor agents in solid tumor therapy.

Research Progress and Perspectives of Antibody-drug Conjugates Targeting Trophoblast Cell Surface Antigen-2 in Advanced Non-small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) remains a significant global health burden, and there is an urgent need for new treatment options. Trophoblast cell surface antigen-2 (TROP-2), a target closely associated with NSCLC prognosis, has become a research hotspot in recent years. Notably, TROP-2-targeted antibody-drug conjugates (ADCs) have made groundbreaking advances in NSCLC therapy. Clinical studies have demonstrated that certain TROP-2 ADCs can significantly improve progression-free survival in previously treated patients with advanced or metastatic NSCLC, regardless of the presence of actionable genomic alterations. These agents have shown promising potential in both frontline and subsequent treatment settings. In terms of safety, while adverse effects affecting the hematologic, respiratory, and gastrointestinal systems are generally manageable, close clinical monitoring and timely management are still required. In conclusion, TROP-2 ADCs hold great promise in the treatment of NSCLC. .

Concurrent EGFR mutation and SMARCA4 deficiency in non-small cell lung cancer: A case report and literature review.

SMARCA4-deficient non-small cell lung cancer (NSCLC) represents a highly aggressive subtype with poor prognosis. While clinical studies have identified common co-mutations in TP53, LRP1B, STK11, KEAP1, and KRAS, actionable driver mutations such as EGFR or ALK are rarely reported in conjunction with SMARCA4 deficiency. This case presents a rare instance of NSCLC featuring both an EGFR exon 21 L858R mutation and SMARCA4 deficiency, highlighting the challenges in treatment and the need for novel therapeutic strategies. A 79-year-old female patient presented with concerns of a lung mass, suspected to be peripheral lung cancer based on diagnostic imaging. Histopathological evaluation confirmed SMARCA4-deficient NSCLC. Molecular genetic analysis further revealed an EGFR exon 21 L858R mutation. The patient was initially treated with osimertinib, an EGFR tyrosine kinase inhibitor. Upon disease progression, treatment was adjusted to include anlotinib in combination with ongoing osimertinib. The initial treatment with osimertinib led to partial remission. However, disease progression necessitated a change in therapy. The combination treatment stabilized the disease temporarily, achieving a stable disease status. This case underscores the transient efficacy of targeted therapy in SMARCA4-deficient NSCLC with concurrent EGFR mutations. It highlights the need for continuous therapeutic adjustments and emphasizes the importance of further research into effective strategies for treating this complex and challenging subset of NSCLC, as current modalities have limitations in sustained efficacy.

Updated overall survival and ctDNA analysis in patients with EGFR T790M-positive advanced non-small cell lung cancer treated with lazertinib in the phase 1/2 LASER201 study.

Lazertinib is a potent, irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with significant efficacy in patients with EGFR T790M-mutated non-small cell lung cancer (NSCLC). This is the final overall survival (OS) report from the phase 1/2 LASER201 study in patients with advanced NSCLC with disease progression on or after prior EGFR TKI therapy. Eligible patients were aged ≥ 20years, with advanced EGFR-mutated NSCLC and previous therapy with EGFR TKI. Patients in this integrated analysis received oral lazertinib 240mg/day. Endpoints included efficacy and safety; exploratory analyses included associations between circulating EGFR-mutant tumor DNA (ctDNA) and efficacy parameters. This integrated analysis included 78 patients in Korea who received second- or later-line lazertinib. The median OS was 38.9months; estimated survival rates at 12, 24, and 36months were 89.5%, 73.9%, and 52.8%, respectively. The cumulative 12-month incidence of central nervous system progression was 9.4%. EGFR-mutant ctDNA was detected in 46 patients (62.2%) at baseline. The presence of ctDNA at baseline significantly predicted progression-free survival (PFS), disease control rate (DCR), and OS. PFS, response rate, and DCR were significantly associated with EGFR-mutant ctDNA clearance at cycle 3; PFS and OS were significantly associated with ctDNA clearance at cycle 5. The safety profile of lazertinib 240mg/day was consistent with previous findings. Lazertinib is a promising treatment option for patients with EGFR T790M-positive NSCLC following disease progression on prior EGFR-directed TKIs. Patients in LASER201 experienced prolonged OS, regardless of their EGFR mutation, brain metastases, or prior brain radiation status. Clearance of plasma EGFR mutations after lazertinib was associated with patient outcomes. ClinicalTrials.gov identifier NCT03046992.