UNASSIGNED: It is still unclear whether KEAP1 mutation is detrimental to immunotherapy of lung adenocarcinoma (LUAD) patients, we try to analyse the exact changes in the TME in LUAD patients with KEAP1 mutations and to identify key factors influencing prognosis.
UNASSIGNED: A total of 1,029 patients with lung squamous carcinoma (LUSC) or LUAD with data obtained from The Cancer Genome Atlas were included in this study. The TME and OS of patients with LUAD stratified by mutant versus wild-type KEAP1 status were comprehensively measured. Moreover, we classified LUAD patients with KEAP1 mutations into three subtypes, by unsupervised consensus clustering. We further analysed the TME, OS, commutated genes and metabolic pathways of different subgroups. A total of 40 LUAD patients underwent immunotherapy were collected and classified into mutant KEAP1 group and wild-type KEAP1 group. We also conducted immunohistochemical staining in KEAP1-MT groups.
UNASSIGNED: Suppressed TME was observed not only in LUAD patients but also in LUSC patients. LUAD patients with mutant KEAP1 underwent immunotherapy had worse PFS than wild-type KEAP1. Unsupervised consensus clustering analysis suggested that the three subtypes of patients exhibited different densities of neutrophil infiltration and had different OS results: cluster 2 patients had significantly higher levels of neutrophils had significantly worse prognoses than those of patients in clusters 1 and 3 and patients with wild-type KEAP1. Univariate and multivariate Cox analyses proved that a high density of neutrophils was significantly associated with worse OS and immunohistochemical staining proved that shorter PFS showed high density of neutrophils.
UNASSIGNED: KEAP1 mutation significantly suppresses the tumour immune microenvironment in LUAD patients. LUAD patients with mutant KEAP1 underwent immunotherapy had worse PFS than with wild-type KEAP1. Neutrophils may play an important role in the prognosis of LUAD patients with KEAP1 mutations and may provide a promising therapeutic target.

Anaplastic lymphoma kinase (ALK) inhibitors are the recommended treatment of ALK-rearranged non-small cell lung cancer but are prone to eventual drug resistance. Herein we report a 45-year-old Asian woman diagnosed with EML4-ALK rearranged lung adenocarcinoma. Small cell lung cancer-like phenotypic transformation occurred when resistance to crizotinib treatment. Next-generation sequencing was performed and detected an ALK rearrangement co-existent with a TP53 gene mutation in the small cell specimens. The patient had a good response to alectinib with a progression-free survival >7 months. After disease progression, newly emerged ALK p.G1269A and p.L1196 M gene mutations co-existent with ALK rearrangement were detected. The patient had a good initial response to ceritinib treatment, which last for >12 months. After ceritinib failure, however, more complicated mutations within the ALK kinase domain (p.G1269A, p.L1196 M, newly emerged p.D1203 N, and p.L1122V) were detected. Ultimately, due to terminal rapid progression and resistance to lorlatinib, the overall survival was nearly 3 years. Our case showed that next-generation ALK-tyrosine kinase inhibitors (TKIs) may be an appropriate choice after transformation to small cell lung cancer and failure to one ALK-TKI. Sequential biopsies and gene mutation monitoring are important to arrange the sequence of different generation ALK-TKIs. Appropriate sequential therapies may yield a prolonged response with a satisfactory quality of life in patients with advanced ALK-rearranged non-small cell lung cancer.

Non-Small Cell Lung Cancer (NSCLC) is a prevalent and deadly form of lung cancer worldwide with a low 5-year survival rate. Current treatments have limitations, particularly for advanced-stage patients. P21, a protein that inhibits the CCND1-CDK4 complex, plays a crucial role in cell proliferation. Computer-Aided Drug Design (CADD) based on pharmacophores can screen and design PPI inhibitors targeting the CCND1-CDK4 complex. By analyzing known inhibitors, key pharmacophores are identified, and computational methods are used to screen potential PPI inhibitors. Molecular docking, pharmacophore matching, and structure-activity relationship studies optimize the inhibitors. This approach accelerates the discovery of CCND1-CDK4 PPI inhibitors for NSCLC treatment. Molecular dynamics simulations of CCND1-CDK4-P21 and CCND1-CDK4 complexes showed stable behavior, comprehensive sampling, and P21\'s impact on complex stability and hydrogen bond formation. A pharmacophore model facilitated virtual screening, identifying compounds with favorable binding affinities. Further simulations confirmed the stability and interactions of selected compounds, including 513457. This study demonstrates the potential of CADD in optimizing PPI inhibitors targeting the CCND1-CDK4 complex for NSCLC treatment. Extended simulations and experimental validations are necessary to assess their efficacy and safety.

The delivery of neoadjuvant and perioperative therapies for non-small cell lung cancer has been radically altered by significant advances and by the incorporation of targeted therapies as well as immune checkpoint inhibitors alone or alongside conventional chemotherapy. This evolution has been particularly notable in the incorporation of immunotherapy and targeted therapy into the treatment of resectable NSCLC, where recent FDA approvals of drugs such as nivolumab and pembrolizumab, in combination with platinum doublet chemotherapy, have led to considerable improvements in pathological complete response rates and the potential for enhanced long-term survival outcomes. This review emphasizes the growing importance of biomarkers in optimizing treatment selection and explores the impact of emerging studies that challenge existing treatment paradigms and investigate novel therapeutic combinations poised to redefine standard of care practices. Furthermore, the discussion extends to the unmet needs within perioperative treatment assessment and prognostication, highlighting the prospective value of biomarkers in evaluating treatment responses and prognosis.

BACKGROUND: Treatment of non-small lung cancer (NSCLC) has evolved in recent years, benefiting from advances in immunotherapy and targeted therapy. However, limited biomarkers exist to assist clinicians and patients in selecting the most effective, personalized treatment strategies. Targeted next-generation sequencing-based genomic profiling has become routine in cancer treatment and generated crucial clinicogenomic data over the last decade. This has made the development of mutational biomarkers for drug response possible.
METHODS: To investigate the association between a patient\'s responses to a specific somatic mutation treatment, we analyzed the NSCLC GENIE BPC cohort, which includes 2,004 tumor samples from 1,846 patients.
RESULTS: We identified somatic mutation signatures associated with response to immunotherapy and chemotherapy, including carboplatin-, cisplatin-, pemetrexed- or docetaxel-based chemotherapy. The prediction power of the chemotherapy-associated signature was significantly affected by epidermal growth factor receptor (EGFR) mutation status. Therefore, we developed an EGFR wild-type-specific mutation signature for chemotherapy selection.
CONCLUSIONS: Our treatment-specific gene signatures will assist clinicians and patients in selecting from multiple treatment options.

Lung cancer is a leading cause of cancer-related death worldwide in both men and women, however mortality in the US and EU are recently declining in parallel with the gradual cut of smoking prevalence. Consequently, the relative frequency of adenocarcinoma increased while that of squamous and small cell carcinomas declined. During the last two decades a plethora of targeted drug therapies have appeared for the treatment of metastasizing non-small cell lung carcinomas (NSCLC). Personalized oncology aims to precisely match patients to treatments with the highest potential of success. Extensive research is done to introduce biomarkers which can predict the effectiveness of a specific targeted therapeutic approach. The EGFR signaling pathway includes several sufficient targets for the treatment of human cancers including NSCLC. Lung adenocarcinoma may harbor both activating and resistance mutations of the EGFR gene, and further, mutations of KRAS and BRAF oncogenes. Less frequent but targetable genetic alterations include ALK, ROS1, RET gene rearrangements, and various alterations of MET proto-oncogene. In addition, the importance of anti-tumor immunity and of tumor microenvironment has become evident recently. Accumulation of mutations generally trigger tumor specific immune defense, but immune protection may be upregulated as an aggressive feature. The blockade of immune checkpoints results in potential reactivation of tumor cell killing and induces significant tumor regression in various tumor types, such as lung carcinoma. Therapeutic responses to anti PD1-PD-L1 treatment may correlate with the expression of PD-L1 by tumor cells. Due to the wide range of diagnostic and predictive features in lung cancer a plenty of tests are required from a single small biopsy or cytology specimen, which is challenged by major issues of sample quantity and quality. Thus, the efficacy of biomarker testing should be warranted by standardized policy and optimal material usage. In this review we aim to discuss major targeted therapy-related biomarkers in NSCLC and testing possibilities comprehensively.

UNASSIGNED: To evaluate the cost-effectiveness of sotorasib versus docetaxel in non-small cell lung cancer (NSCLC) patients with KRASG12C mutation from the China and United States\'social perspective.
UNASSIGNED: A Markov model that included three states (progression-free survival, post-progression survival, and death) was developed. Incremental cost-effectiveness ratio (ICER), quality-adjusted life-year (QALY), and incremental QALY were calculated for the two treatment strategies. One-way sensitivity analysis was used to investigate the factors that had a greater impact on the model results, and tornado diagrams were used to present the results. Probabilistic sensitivity analysis was performed with 1,000 Monte Carlo simulations. Assume distributions based on parameter types and randomly sample all parameter distributions each time., The results were presented as cost-effectiveness acceptable curves.
UNASSIGNED: This economic evaluation of data from the CodeBreak 200 randomized clinical trial. In China, sotorasib generated 0.44 QAYL with a total cost of $84372.59. Compared with docetaxel, the ICER value of sotorasib was $102701.84/QALY, which was higher than willingness to pay (WTP), so sotorasib had no economic advantage. In the US, sotorasib obtained 0.35 QALY more than docetaxel, ICER was $15,976.50/QALY, which was more than 1 WTP but less than 3 WTP, indicating that the increased cost of sotorasib was acceptable. One-way sensitivity analysis showed that the probability of sotorasib having economic benefits gradually increased when the cost of follow-up examination was reduced in China. And there was no influence on the conclusions within the range of changes in China. When the willingness to pay (WTP) exceeds $102,500, the probability of sotorasib having cost effect increases from 0% to 49%.
UNASSIGNED: Sotorasib had a cost effect from the perspective in the United States. However, sotorasib had no cost effect from the perspective in China, and only when the WTP exceeds $102,500, the probability of sotorasib having cost effect increases from 0% to 49%.

UNASSIGNED: Angiogenesis plays an important role in the occurrence and development of non-small cell lung cancer (NSCLC). The atypical mitogen-activated protein kinase 4 (MAPK4) has been shown to be involved in the pathogenesis of various diseases. However, the potential role of MAPK4 in the tumor angiogenesis of NSCLC remains unclear.
UNASSIGNED: Adult male C57BL/6 wild-type mice were randomly divided into the control group and p-siMAPK4 intervention group, respectively. The cell proliferation was analyzed with flow cytometry and immunofluorescence staining. The vascular density in tumor mass was analyzed by immunofluorescence staining. The expressions of MAPK4 and related signaling molecules were detected by western blot analysis and immunofluorescence staining, and so on.
UNASSIGNED: We found that the expression of MAPK4, which was dominantly expressed in local endothelial cells (ECs), was correlated with tumor angiogenesis of NSCLC. Furthermore, MAPK4 silencing inhibited the proliferation and migration abilities of human umbilical vein ECs (HUVECs). Global gene analysis showed that MAPK4 silencing altered the expression of multiple genes related to cell cycle and angiogenesis pathways, and that MAPK4 silencing increased transduction of the extracellular regulated protein kinases 1/2 (ERK1/2) pathway but not Akt and c-Jun n-terminal kinase pathways. Further analysis showed that MAPK4 silencing inhibited the proliferation and migration abilities of HUVECs cultured in tumor cell supernatant, which was accompanied with increased transduction of the ERK1/2 pathway. Clinical data analysis suggested that the higher expression of MAPK4 and CD34 were associated with poor prognosis of patients with NSCLC. Targeted silencing of MAPK4 in ECs using small interfering RNA driven by the CD34 promoter effectively inhibited tumor angiogenesis and growth of NSCLC in vivo.
UNASSIGNED: Our results reveal that MAPK4 plays an important role in the angiogenesis and development of NSCLC. MAPK4 may thus represent a new target for NSCLC.

UNASSIGNED: Non-small cell lung Cancer (NSCLC) persists as a lethal neoplastic manifestation, exhibiting a diminished 5-year survival rate, partially attributable to chemotherapeutic resistance. This investigative endeavor aimed to elucidate the synergistic antineoplastic effects and underlying mechanisms of the SMYD2 inhibitor BAY-598 and the chemotherapeutic agent doxorubicin (DOX) in NSCLC.
UNASSIGNED: The human non-small cell lung cancer cell lines A549 and H460 were subjected to treatment regimens involving BAY-598 and/or DOX. Cellular viability, apoptotic events, invasive capacity, and migratory potential were evaluated through the implementation of CCK-8 assays, flow cytometric analyses, and Transwell assays, respectively. Protein expression levels were quantified via Western blot analyses. An in vivo xenograft murine model was established to assess therapeutic efficacy.
UNASSIGNED: BAY-598 and DOX synergistically suppressed the viability, invasiveness, and migratory capabilities of NSCLC cells. Co-treatment Promoting cell apoptosis and cell cycle arrest. Additionally, Furthermore, co-administration significantly inhibited cell migration and invasion. Mechanistic studies revealed coordinately inhibited JAK-STAT signaling upon combination treatment. In vivo study further validated the synergistic antitumor efficacy of BAY-598 and DOX against NSCLC xenografts.
UNASSIGNED: Our findings demonstrate that BAY-598 potentiates the anti-cancer effects of DOX in non-small cell lung cancer cells by modulating the JAK/STAT signaling pathway as a synergistic strategy. The combination holds promise as an emerging therapeutic strategy for NSCLC. Further optimization and validation are warranted to promote its translational potential.

UNASSIGNED: Activating mutations in epidermal growth factor receptor (EGFR) have been identified as key predictive biomarkers for the customized treatment with EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), aiding in improving patient response rates and survival. However, resistance challenges the efficacy of these treatments, with limited understanding of post-resistance therapeutic strategies. A deep understanding of the biology and resistance mechanisms of EGFR-mutant NSCLC is crucial for developing new treatment approaches. This study, through bibliometric analysis, summarizes the trends in research on resistance to EGFR-TKIs.
UNASSIGNED: Research papers on NSCLC with EGFR inhibitor resistance were collected from the Web of Science Core Collection (WoSCC). The analysis utilized bibliometric tools like CiteSpace, VOSviewer, and other platforms for comprehensive analysis and visualization of the outcomes.
UNASSIGNED: The WoSCC database contains a total of 5866 documents on resistance to EGFR-TKIs treatment, including 4727 articles (93.48%) and 1139 reviews (6.52%), spanning 81 countries and regions, 4792 institutions, with the involvement of 23,594 authors. Since 2016, there has been a significant increase in publications in this field. China has the highest publication output, while the United States has the highest citation count for papers. Harvard University leads in terms of the number of publications. Among the top ten journals with the highest output, Clinical Cancer Research has the highest impact factor at 11.5, with 90% of the journals classified in Q1 or Q2. Rafael Rosell is one of the most influential authors in this field, ranking second in publication volume and fourth in citation count. Research on EGFR-TKIs resistance mainly focuses on genetic testing, resistance mechanisms, and post-resistance treatment strategies.
UNASSIGNED: This study provides researchers with a reliable basis and guidance for finding authoritative references, understanding research trends, and exploring potential directions.