Globally, osimertinib resistance has been a long-term challenge. Resveratrol, a naturally occurring polyphenolic compound found in various plants, has the potential to modulate multidrug resistance mechanisms. However, the specific role of resveratrol in delaying osimertinib resistance in lung cancer is still unclear. The present study aimed to investigate the therapeutic effects and underlying mechanisms of resveratrol in delaying osimertinib resistance. Accordingly, the corresponding targets of resveratrol were screened through the Traditional Chinese Medicine Systems Pharmacology database. Similarly, the corresponding targets for osimertinib resistance were mined from the GeneCards database. A protein-protein interaction network was subsequently constructed to pinpoint key hub genes that resveratrol may target to delay resistance. Molecular docking analysis was then employed to assess the binding energy between the predicted key targets and resveratrol. Finally, in vitro experiments were performed to validate the results. Ultimately, 13 potential therapeutic targets of resveratrol related to delaying osimertinib resistance were identified. Kyoto Encyclopedia of Genes and Genomes analysis suggested that the effects of resveratrol may be associated with the apoptotic pathway. Molecular docking revealed that resveratrol has good binding affinities with MCL1 and BCL2L11. In vitro experiments confirmed that resveratrol inhibited the proliferation of osimertinib-resistant cells and upregulated the expression of BCL2L11. In conclusion, resveratrol may promote apoptosis by targeting BCL2L11 to delay osimertinib resistance.

Non-small cell lung cancer (NSCLC) is a common cause of cancer-related deaths worldwide, and its incidence has been increasing in recent years. While targeted therapies like osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor, have brought about notable improvements in patient outcomes for advanced NSCLC, the challenge of acquired drug resistance persists. Here, we found that cellular mesenchymal-epithelial transition factor (c-Met) was highly expressed in osimertinib-resistant cells, and depletion of c-Met markedly inhibited the growth of osimertinib-resistant cells ex vivo and in vivo, suggesting that c-Met is a potential target to address osimertinib resistance. Through a screening process using a natural product compound library, we identified piperlongumine as a potent inhibitor to overcome osimertinib resistance. Furthermore, the combined treatment of piperlongumine and osimertinib exhibited robust antitumor effects in resistant cells, partially restoring their sensitivity to osimertinib. Additionally, we discovered that piperlongumine could enhance the interaction between E3 ligase RNF4 and Sp1, inhibit the phosphorylation of Sp1 at Thr739, facilitate the ubiquitination and degradation of Sp1, lead to c-Met destabilization, and trigger intrinsic apoptosis in resistant cells. In summary, our study sheds light on the potential of piperlongumine in overcoming osimertinib resistance, offering new strategies and perspectives for the clinical management of drug-resistant NSCLC.

Most non-small cell lung cancer patients have epidermal growth factor receptor (EGFR) activating mutations, such as exon 19 deletion and exon 21 replacement mutations. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitors approved for the treatment of lung cancer patients carrying EGFR activating mutations. Osimertinib-induced interstitial lung disease (ILD) is a rare and potentially fatal pulmonary toxic manifestation of drug therapy. At present, there is no international consensus on the risks and treatment of the osimertinib-induced ILD.

We report a case of a 56-year-old woman who was diagnosed with lung adenocarcinoma with lung hilum, mediastinal lymph nodes and brain metastases (T4N3M1c stage IVB). The patient received targeted treatment with osimertinib after radiotherapy and chemotherapy. But she developed ILD after osimertinib treatment. Following active symptomatic treatment and hormone treatment, the lung injury alleviated. The patient was retreated with furmonertinib combined with prednisone and did not experience ILD again. So far, she has survived for 14 months without disease progression.

Retreatment with furmonertinib under prednisone could be considered as an effective therapeutic option after risk-benefit assessment for EGFR-mutant lung adenocarcinoma patients.

"Epidermal growth factor receptor (EGFR)" mutations are pivotal in the pathogenesis of "Non-Small Cell Lung Cancer (NSCLC)," which is associated with high morbidity and mortality rates. The advent of third and fourth-generation EGFR tyrosine kinase inhibitors (TKIs) has significantly advanced the therapeutic landscape for EGFR-mutant NSCLC, particularly in overcoming resistance mutations such as T790M and C797S. This review delves into the current clinical status, efficacy, safety profiles, and regulatory approvals of third-generation EGFR TKIs, including Osimertinib, Lazertinib, Furmonertinib, Aumolertinib, Rezivertinib, Befotertinib, Sunvozertinib. Furthermore, it explores emerging fourth-generation EGFR TKIs designed to address resistance mechanisms beyond those targeted by their predecessors. Notable fourth-generation candidates such as TQB3804, BPI-361175, BDTX-1535, WJ13404, QLH11811, H002, HS-10375, BBT-207, JIN-A02, and HS-10504 are highlighted for their potential to overcome the C797S mutation. The review emphasizes the importance of these advanced inhibitors in enhancing "progression-free survival and overall survival rates". By evaluating the therapeutic potential and limitations of these EGFR TKIs, this review aims to guide future research in the management of EGFR-mutant NSCLC. This acts as guiding beacon for the strategic design and development of third and fourth generation EGFR-TK inhibitors to overcome the drug resistance hurdles in the development of EGFR-TK inhibitors.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are remarkably effective for treating EGFR-mutant non-small cell lung cancer (NSCLC). However, patients inevitably develop acquired drug resistance, resulting in recurrence or metastasis. It is important to identify novel effective therapeutic targets to reverse acquired TKI resistance.

Bioinformatics analysis revealed that nicotinamide N-methyltransferase (NNMT) was upregulated in EGFR-TKI resistant cells and tissues via EGR1-mediated transcriptional activation. High NNMT levels were correlated with poor prognosis in EGFR-mutated NSCLC patients, which could promote resistance to EGFR-TKIs in vitro and in vivo. Mechanistically, NNMT catalyzed the conversion of nicotinamide to 1-methyl nicotinamide by depleting S-adenosyl methionine (the methyl group donor), leading to a reduction in H3K9 trimethylation (H3K9me3) and H3K27 trimethylation (H3K27me3) and subsequent epigenetic activation of EGR1 and ALDH3A1. In addition, ALDH3A1 activation increased lactic acid levels, which further promoted NNMT expression via p300-mediated histone H3K18 lactylation on its promoter. Thus, NNMT mediates the formation of a double positive feedback loop via EGR1 and lactate, EGR1/NNMT/EGR1 and NNMT/ALDH3A1/lactate/NNMT. Moreover, the combination of a small-molecule inhibitor for NNMT (NNMTi) and osimertinib exhibited promising potential for the treatment of TKI resistance in an NSCLC osimertinib-resistant xenograft model.

The combined contribution of these two positive feedback loops promotes EGFR-TKI resistance in NSCLC. Our findings provide new insight into the role of histone methylation and histone lactylation in TKI resistance. The pivotal NNMT-mediated positive feedback loop may serve as a powerful therapeutic target for overcoming EGFR-TKI resistance in NSCLC.

Non-small cell lung cancer (NSCLC) is a prevalent and lethal malignancy worldwide, posing significant challenges to patient survival. Recent advancements in the field of oncology have introduced immunotherapy and targeted therapy as primary treatment modalities for NSCLC. However, the emergence of treatment resistance and relapse has impeded their long-term effectiveness. Antibody-drug conjugates (ADCs), a rapidly evolving class of anti-cancer agents, offer a promising solution to this issue by harnessing the specificity of monoclonal antibodies and the cytotoxic potency of drug payloads. ADCs have demonstrated notable potential in targeting both highly expressing and low-expressing malignant cells, with early-phase clinical trials yielding superior survival outcomes in NSCLC patients. This review comprehensively outlines the recent advancements in ADC-based strategies for managing NSCLC, supported by evidence from clinical trials. Additionally, the review delves into the oncogenic mechanisms of various biomarkers and offers insights into strategies for their detection in NSCLC patients. Lastly, a forward-looking perspective is provided to address the challenges associated with the utilization of ADCs in NSCLC therapy.

Third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for patients harboring T790M after first-generation EGFR-TKI resistance. However, the impact of acquired EGFR amplification on the efficacy of third-generation EGFR-TKI against T790M remains uncertain. We aimed to investigate whether the presence of acquired EGFR amplification after first-generation EGFR-TKI resistance influences the efficacy of third-generation EGFR-TKI in patients with advanced non-small-cell lung cancer (NSCLC). We reviewed data from 275 advanced NSCLC patients harboring T790M after first-generation EGFR-TKI resistance. Patients were categorized into two groups based on the presence or absence of acquired EGFR amplification identified through next-generation sequencing (NGS) after first-line EGFR-TKI treatment. We evaluated the efficacy of osimertinib used as a second-line treatment. Among these patients, 59 exhibited acquired EGFR amplification, while 216 did not. The median progression-free survival (PFS) was 12.20 months in the EGFR amplification group and 12.03 months in the non-amplification group (p = 0.011), with median overall survival (OS) of 33.90 months and 23.30 months, respectively (p = 0.164). Multivariate analysis of PFS revealed that acquired EGFR amplification and EGFR 19del were independent prognostic factors for patients with T790M undergoing osimertinib. Additionally, subgroup analysis indicated a prolonged PFS in patients with EGFR 19del compared to those with EGFR 21L858R (p = 0.034) in the EGFR amplification group. Following first-generation EGFR-TKI resistance, advanced EGFR-mutant NSCLC patients harboring both acquired T790M and EGFR amplification are likely to experience enhanced PFS with osimertinib. This phenomenon is particularly noteworthy among individuals with EGFR 19del.

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC) patients, which remarkably improve the clinical outcomes. However, drug resistance has greatly impaired the efficacy of EGFR-TKIs and contributes to cancer treatment failure. DUSP1, a negative regulator of MAPK signaling pathway, was discovered to mediate drug resistance in multiple types of cancers. Our study aimed to explore the role of DUSP1 in NSCLC cell resistance to osimertinib, a third-generation EGFR-TKI. Human NSCLC cell lines PC-9 and HCC827 were exposed to increasing concentrations of osimertinib for over 6 months to generate osimertinib resistant cells (PC-9-OR and HCC827-OR). The viabilities of osimertinib-resistant and parental sensitive NSCLC cells in response to osimertinib stimulation were detected by MTS assay and the IC50 values for osimertinib were obtained. The differentially expressed genes in osimertinib-resistant and sensitive NSCLC cells were identified by analyzing the GEO dataset GSE106765 using bioinformatic tools. DUSP1 expression was knocked down by using the short hairpin RNAs (shRNAs). Then, the effects of DUSP1 silencing on osimertinib-resistant and sensitive NSCLC cell resistance to osimertinib, viability, proliferation and apoptosis were assessed through loss-of-function experiments. The expression of key molecules (JNK, ERK, and p38 MAPK) in the MAPK signaling pathway was detected through western blotting analysis. DUSP1 was overexpressed in osimertinib-resistant NSCLC cells versus parental sensitive cells. DUSP1 silencing attenuated the resistance of NSCLC cells to osimertinib. DUSP1 silencing markedly inhibited osimertinib-resistant and sensitive NSCLC cell proliferation but enhanced cell apoptosis. Mechanically, DUSP1 knockdown increased phosphorylated-JNK, ERK, and p38 MAPK levels in NSCLC cells. Treatment with SB203580, the p38 MAPK inhibitor, reversed the effects of DUSP1 silencing on osimertinib-resistant NSCLC cell resistance to osimertinib, cell proliferation and apoptosis. DUSP1 downregulation restores the sensitivity of NSCLC cells to osimertinib via activating the MAPK signaling pathway.

Gansui [Euphorbia kansui T. N. Liou ex S.B.Ho (Euphorbiaceae)] has been reported to inhibit the proliferation of non-small cell lung cancer (NSCLC) cells; however, its underlying pharmacological mechanism remains unclear.

To investigate the potential effects and mechanisms of Gansui in blocking NSCLC progression.

The targets of Gansui's components and NSCLC-related targets were obtained through public database and published studies. Functional enrichment analysis was performed using the clusterProfiler R package. STRING database was used for protein-protein interaction analysis. CytoHubba plugin was applied to get the hub genes. Molecular docking was applied to assess the binding affinities between the hub targets and the crucial components. Kidjolanin was used to treat A549 and NCI-H1385, and its effects on cell viability, sensitivity of paclitaxel and expression levels of hub genes were investigated by cell counting kit-8 assay, flow cytometry and qPCR.

A total of 16 Gansui active ingredients and 337 targets were collected, of which 298 targets overlapped with NSCLC-related genes. STAT3, EGFR, GRB2, AKT2, AKT3 and PIK3CA were identified as hub genes. The components in Gansui, including kidjoranin 3-O-β-digitoxopyranoside, cynotophylloside B, 13-Oxyingenol-dodecanoate, and kidjolanin had good binding affinity with the hub targets. Kidjolanin inhibited the viability of NSCLC cells, promoted apoptosis and inhibited the expression of hub genes. Kidjolanin also enhanced the proliferation inhibition and apoptosis of NSCLC cells induced by paclitaxel.

Gansui exerts anti-NSCLC effects via multiple downstream targets, implying its potential in NSCLC treatment.

Methylthioadenosine phosphorylase (MTAP) is an essential metabolic enzyme in the purine and methionine salvage pathway. In cancer, MTAP gene copy number loss (MTAP loss) confers a selective dependency on the related protein arginine methyltransferase 5. The impact of MTAP alterations in gastrointestinal (GI) cancers remains unknown although hypothetically druggable. Here, we aim to investigate the prevalence, clinicopathological features and prognosis of MTAP loss GI cancers.

Cases with MTAP alterations were retrieved from The Cancer Genome Atlas (TCGA) and a real-world cohort of GI cancers profiled by next-generation sequencing. If MTAP alterations other than loss were found, immunohistochemistry was performed. Finally, we set a case-control study to assess MTAP loss prognostic impact.

Findings across the TCGA dataset (N=1363 patients) and our cohort (N=508) were consistent. Gene loss was the most common MTAP alteration (9.4%), mostly co-occurring with CDKN2A/B loss (97.7%). Biliopancreatic and gastro-oesophageal cancers had the highest prevalence of MTAP loss (20.5% and 12.7%, respectively), being mostly microsatellite stable (99.2%). In colorectal cancer, MTAP loss was rare (1.1%), while most MTAP alterations were mutations (5/7, 71.4%); among the latter, only MTAP-CDKN2B truncation led to protein loss, thus potentially actionable. MTAP loss did not confer worse prognosis.

MTAP alterations are found in 5%-10% of GI cancers, most frequently biliopancreatic and gastro-oesophageal. MTAP loss is the most common alteration, identified almost exclusively in MSS, CDKN2A/B loss, upper-GI cancers. Other MTAP alterations were found in colorectal cancer, but unlikely to cause protein loss and drug susceptibility.

Mutant EGFR is a common driver of non-small cell lung cancer (NSCLC). Although mutant EGFR has been reported to limit the efficacy of immunotherapy, a subset of patients with EGFR-mutant NSCLC benefit from treatment with immune checkpoint inhibitors. A better understanding of how co-occurring genomic alterations in oncogenic driver genes impact immunotherapy efficacy may provide a more complete understanding of cancer heterogeneity and identify biomarkers of response. Here, we investigated the effects of frequent EGFR co-mutations in EGFR-mutant lung cancer models and identified loss-of-function mutation of CDKN2A as a potential sensitizer to anti-PD-1 treatment in vitro and in vivo. Mechanistically, CDKN2A loss impacted the composition of the tumor immune microenvironment by promoting the expression of PD-L2 through reduced ubiquitination of c-MYC, and mutant EGFR cooperating to upregulate c-MYC and PD-L2 by activating the MAPK pathway. Blocking PD-L2 induced antitumor immune responses mediated by CD8+ T cells in EGFR/CDKN2A co-mutated lung cancer. Importantly, a small-molecule PD-L2 inhibitor, zinc undecylenate, remodeled the tumor immune microenvironment of EGFR/CDKN2A co-mutant tumors and enhanced the antitumor efficacy of EGFR tyrosine kinase inhibitors. Collectively, these results identify EGFR/CDKN2A co-mutation as a distinct subtype of NSCLC that shows superior sensitivity to immune checkpoint blockade and reveals a potential combined therapeutic strategy for treating this NSCLC subtype. Significance: Upregulation of c-MYC driven by co-mutation of CDKN2A and EGFR increases PD-L2 to abrogate CD8+ T-cell activity in lung cancer, which confers sensitivity to PD-L2 blockade in combination with tyrosine kinase inhibitors.

Skin toxicities are the most common adverse effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). While EGFR-TKIs induce pyroptosis in lung cancer cells through Gasdermin E (GSDME) activation, it is unknown whether they can similarly affect skin cells. In this study, we used immunohistochemistry to demonstrate that in acneiform rash, the N-terminus of GSDME (GSDME-N) is predominantly expressed in the basal layer of the follicular epithelium and sebocytes, while it is absent in the interfollicular epidermis. In contrast, in cases of xerosis or secondary eczematous rash, GSDME-N was significantly expressed in the basal layer of the interfollicular epidermis and weakly or partially positive in the follicular epithelium. Bright-field microscopy of HaCaT and SZ95 cells treated with afatinib revealed cell swelling and large bubble formation, while scanning electron microscopy showed a reduction in microvilli and membrane pores formation. Transmission electron microscopy further revealed multiple membrane pores and decreased cytoplasmic density. Importantly, we found that GSDME is cleaved during afatinib-induced pyroptosis via caspase-3 activation. ELISA analysis further confirmed that afatinib-treated cells released elevated levels of HMGB1 and IL-1α. Meanwhile, inhibition of caspase-3 activity or knockdown of GSDME both suppressed afatinib-induced pyroptosis, while GSDME elimination did not affect caspase-3 activation. These results indicate that afatinib-induced pyroptosis in keratinocytes and sebocytes is mediated by the caspase-3/GSDME pathway. Our findings suggest that GSDME-dependent pyroptosis in HaCaT and SZ95 cells contributes to the development of acneiform rash and xerosis, highlighting the need for further investigation into the underlying mechanisms.

Overcoming acquired resistance to Osimertinib remains a critical challenge in treating NSCLC. This research indicates that Osimertinib-resistant cells exhibit a strong dependence on glutamine metabolism. However, targeting GLS1 shows limited anticancer effects, probably because it cannot fully block the glutamine metabolic pathway. The investigation reveals that a more effective strategy involves simultaneously inhibiting both ASCT2 and GLS1. After confirming the efficacy of this dual-targeting approach against Osimertinib-resistant cells in preclinical models, the potential of utilizing a broad-spectrum glutamine metabolism antagonist is further explored to achieve superior antitumor efficacy. DON, broad-spectrum glutamine antagonist, presents toxicity issues. Herein, the high NQO1 expression in Osimertinib-resistant NSCLC cells is leveraged to design an NQO1-responsive DON prodrug, 10e (LBJ-10e). This prodrug demonstrates superior safety compared to natural DON and greater antitumor activity against resistant tumors compared to the clinical phase II drug DRP104. These findings may address the clinical limitations of GLS1 allosteric inhibitors and underscore prodrug strategies in effectively treating Osimertinib-resistant lung cancer, providing a foundation for future clinical trials.

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.

Lung adenocarcinoma (LUAD) poses a significant therapeutic challenge, primarily due to delayed diagnosis and the limited efficacy of existing treatments.

To understand the pathogenesis and identify diagnostic biomarkers for LUAD in the early stage, we investigated differential miRNA expression in 33 stage I LUAD patients between tumor and matched paracancerous tissues by Illumina Sequencing. Target genes of differentially expressed miRNAs were predicted using TargetScan and miRDB databases and further analyzed by GO and KEGG pathway enrichment analysis. The miRNAs expression results were verified using qRT-PCR. Additionally, we evaluated the clinical significance of miRNAs by the TCGA database. miR-183-3p was chosen for subsequent biological functional studies by cell proliferation assays, cell migration and cell invasion assays, cell apoptosis and cell cycle assays in LUAD cells. The clinical relevance target genes of miR-183-3p were predicted by TargetScan databases and bioinformatics assays. Gene-specific experimental validation was performed using qRT-PCR, western blotting and luciferase reporter assays.

We identified 36 differentially expressed miRNAs between LUAD tissues and matched paracancerous tissues. Target genes for these miRNAs revealed associations with processes and pathways such as RNA biosynthesis, intracellular signaling, protein transport, and the Ras, MAPK, and PI3K-AKT pathways. The qRT-PCR results were in alignment with the sequencing data for 19 out of these 21 miRNAs which not yet implicated in LUAD, 13 were up-regulated, 6 were down-regulated. The clinical relevance assays showed that 5 up-regulated miRNAs have diagnostic value for LUAD. miR-183-3p showed significant advantages in the result of sequencing, qRT-PCR, and clinical relevance assay. Biological functional assays showed that miR-183-3p emerged as a key regulator, promoting LUAD cell proliferation, decreasing apoptosis, and augmenting migration and invasion capabilities. The clinical relevance assays and experimental validation showed SESN1 as a clinical significance target of miR-183-3p.

Our study lays the foundation for investigating miRNAs with diagnostic significance in early-stage LUAD, pointing out that inhibition of miR-183-3p may serve as a novel therapeutic in LUAD.

Although third-generation Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) is standard of care for patients with EGFR-mutant Non-small cell lung cancer (NSCLC), little is known about the predictors of response or resistance. Here, we integrated single-cell RNA (scRNA) sequencing, bulk RNA sequencing, multiplexed immunofluorescence and flow cytometry data from pretreatment and post-resistant tumor samples of EGFR-mutant NSCLC patients received third-generation EGFR-TKIs. We show that resistant samples had a markedly enriched CXCR1+ neutrophils infiltration (P < 0.01) than pretreatment samples, which were distinguished from other subtypes of neutrophils and displayed immunosupressive characteristics. Spatial analysis showed that increased CXCR1+ neutrophils predominantly infiltrated into the tumor core in resistant samples and the average distance of neutrophils to tumor cells markedly reduced from 33 to 19 μm. Deep analysis of scRNA and bulk RNA sequencing data revealed the increased interactions between CXCR1+ neutrophils and tumor cells and activated TNF-α/NF-κB signaling pathway in tumor cells of resistant samples. In vitro and in vivo experiments validated that CXCR1+ neutrophils resulted in resistance to third-generation EGFR-TKI via activating TNF-α/NF-κB signaling pathway in tumor cells. Importantly, patients with low pretreatment CXCR1+ neutrophil infiltration abundance had a dramatically longer progression-free survival (11.8 vs. 7.5 months; P = 0.019) and overall survival (33.0 vs. 23.5 months; P = 0.029) than those with high infiltration abundance. Collectively, these findings suggest that CXCR1+ neutrophils infiltration was associated with the efficacy of third-generation EGFR-TKI in patients with EGFR-mutant NSCLC.

Clear cell renal cell carcinoma (ccRCC) is a challenging malignancy characterized by intricate biology and clinical characteristics. Despite advancements in treatment strategies, the molecular mechanisms underlying ccRCC initiation, progression, and therapeutic resistance remain elusive. Inflammasomes, multi-protein complexes involved in innate immunity and inflammation, have emerged as potential regulators in cancers. However, their involvement and mechanisms in ccRCC remain poorly understood. In this study, we conducted a systematic investigation into the expression patterns and clinical significance of inflammasome complexes in ccRCC. We found the perturbation of inflammasome complexes genes was related to patient's prognosis and other clinical characteristics. By developing an Inflammasome Complexes (IFC) score and identifying IFC subtypes with distinct clinical characteristics and oncogenic roles, our study suggested that inflammasome activation could impact tumorigenesis and modulate the tumor immune landscape, particularly its positive correlations with immunosuppressive macrophages. Furthermore, our study revealed the potential of inflammasome complex genes as predictive markers for patient responses to various anti-tumor drugs, including Osimertinib, Ulixertinib, Telomerase Inhibitor IX, and GSK2578215A. These findings have significant clinical implications and offer opportunities for guiding treatment strategies and improving patient outcomes of ccRCC.

To systematically evaluate the efficacy and safety of osimertinib plus bevacizumab in treating advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations.

Up to May 26, 2024, the databases of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, Chinese Biomedical Literature, China Science and Technology Journal, and Wanfang were searched, and the randomized controlled clinical trials (RCTs) of osimertinib plus bevacizumab in the treatment of advanced EGFR-mutant NSCLC were included. Two researchers independently screened the literature, assessed the quality of the included literature, and extracted the literature data. Revman5.4 software was used for meta-analysis.

A total of 824 patients were included in 10 RCTs. The results of meta-analysis showed that compared with the control group (osimertinib alone), the experimental group (osimertinib plus bevacizumab) had a higher objective response rate (ORR) (relative risk [RR] = 1.23, 95% confidence interval [CI] = 1.03-1.47, P = .02), and the experimental group could significantly reduce the expression levels of carcinoembryonic antigen (mean difference [SMD] = 0.82, 95% CI = 0.30-1.35, P = .002), vascular endothelial growth factor (SMD = 0.43, 95% CI = 0.13-0.73, P = .005), neuron-specific enolase (SMD = 0.88, 95% CI = 0.60-1.17, P < .00001), cytokeratin 19 fragments (SMD = 1.33, 95% CI = 0.34-2.33, P = .009), and carbohydrate antigen 125 (SMD = 0.46, 95% CI = 0.15-0.77, P = .004) in serum. However, the experimental group did not significantly improve the disease control rate (DCR) (RR = 1.17, 95% CI = 1.00-1.36, P = .05), 1- and 2-year progression-free survival (PFS) rates (RR = 1.15, 95% CI = 1.00-1.33, P = .05; RR = 1.02, 95% CI = 0.74-1.40, P = .92), 1- and 2-year overall survival (OS) rates (RR = 1.11, 95% CI = 0.92-1.36, P = .28; RR = 0.99, 95% CI = 0.84-1.18, P = .95). Interestingly, the results of subgroup analysis showed that the experimental group significantly improved ORR, DCR, 1-year PFS, and OS rates in the Chinese population and patients under 65 years old (P < .05). In addition, when the dose of bevacizumab was 7.5 mg/kg q3w in the experimental group, ORR, DCR, 1-year PFS, and OS rates were significantly better than those in the control group (P < .05). In terms of adverse events of drugs, the incidence of proteinuria, hypertension, oral mucositis, bleeding, nausea, and vomiting in the experimental group was higher than that in the control group (P < .05).

For patients with advanced EGFR-mutant NSCLC, osimertinib plus bevacizumab has some clinical benefit compared with osimertinib alone. Still, it does not provide additional long-term survival benefits and has higher toxicity. More well-designed, multicenter RCTs are needed to identify the subgroups of patients most likely to benefit from this combination regimen and to validate the optimal dose of this combination regimen.

Anlotinib demonstrated encouraging therapeutic activity as third-line treatment for patients with advanced non-small cell lung cancer (NSCLC). Programmed cell death protein 1 (PD-1) inhibitors also exhibited promising and durable response against previously-treated advanced NSCLC. Therefore, the present study aimed to determine the feasibility and safety of anlotinib plus PD-1 inhibitors for previously-treated NSCLC in clinical practice.

This retrospective study included 56 patients with advanced NSCLC treated with systemic treatment previously. Patients included were treated with anlotinib plus PD-1 inhibitors in clinical practice. Therapeutic outcomes of the patients were evaluated radiologically using target lesions, and the prognostic outcomes were generated by follow-up. Adverse reactions experienced throughout the treatment were documented and analyzed.

Between August 2018 and November 2022, 56 patients with advanced NSCLC were eligible to participate in this study consecutively. Therapeutic outcomes resulted in an overall response rate of 28.6% [95% confidence interval (CI): 17.3%-42.2%] and a disease control rate of 91.1% (95% CI: 80.4%-97.0%). Furthermore, this combination regimen among the 56 patients yielded a median progression-free survival (PFS) of 6.5 months (95% CI: 4.81-8.19) and a median overall survival (OS) of 15.8 months (95% CI: 10.23-21.37), respectively. And the median duration of response (DoR) among patients who responded was 8.3 months (95% CI: 4.38-12.22). Additionally, adverse reactions of all grades throughout the treatment were observed in 50 patients (89.3%), and adverse reactions of grade ≥3 were detected in 23 patients (41.1%). Fatigue, hypertension, diarrhea, nausea, and vomiting were the most common adverse reactions. Association analysis between PFS and baseline characteristic subgroups indicated that ECOG score and number of metastatic lesions might be potential predictors of PFS in the exploratory analysis.

Anlotinib plus PD-1 inhibitors demonstrated a tolerable safety profile and encouraging therapeutic activity as subsequent-line therapy in patients with advanced NSCLC. This conclusion should be confirmed in prospective large-scale clinical trials subsequently.

Osimertinib, one of the third-generation EGFR-tyrosine kinase inhibitors (TKIs) designed to target EGFR T790M mutation, significantly improves the prognosis of lung cancer. However, drug resistance still happens and MET amplification is responsible for one of the main causes. Fluorescence in situ hybridization (FISH) is the gold standard for MET amplification detection, but fundamentally limited by observer subjectivity. Herein, we assessed the value of next-generation sequencing (NGS) method in MET amplification detection in non-small cell lung cancer (NSCLC), as well as revealed the mutation profiling of NSCLC patients with osimertinib resistance to provide some valuable clues to the mechanisms of resistance.

A total of 317 cancer tissue samples from 317 NSCLC patients at time of progression following osimertinib were submitted to NGS and only 96 tissues were tested by FISH simultaneously. With FISH results as gold standard, enumeration algorithm was applied to establish the optimal model for identifying MET amplification using gene copy number (GCN) data.

The optimal model for identifying MET amplification was constructed based on the GCN of MET, BRAF, CDK6 and CYP3A4, which achieved a 74.0% overall agreement with FISH and performed well in identifying MET amplification except polysomy with a sensitivity of 85.7% and a specificity of 93.9%. The inconsistency between NGS and FISH occurred mainly in polysomy subtype, while MET GCN ≥ 5 could be reliably recognized by NGS. Moreover, the most frequently mutated genes in NSCLC patients with osimertinib resistance were EGFR (59.94%), followed by TP53 (43.85%), NRG1 (9.46%), PIK3CA (6.31%), and ATM (5.36%). The known resistance mechanisms, including MET amplification, EGFR (C797S, L718Q/R), TP53, CDK4, CDK6, CDKN2A, BRAF, KRAS, NRAS and PIK3CA mutations were also disclosed in our cohort.

NGS assay can achieve a high concordance with FISH in MET amplification detection and has advantages in portraying various genetic alterations, which is of worthy in clinical promotion.

Protein shuttling between the cytoplasm and nucleus is a unique phenomenon in eukaryotic organisms, integral to various cellular functions. Membrane-bound transcription factors (MTFs), a specialized class of nucleocytoplasmic shuttling proteins, are anchored to the cell membrane and enter the nucleus upon ligand binding to exert their transcriptional regulatory functions. MTFs are crucial in cellular signal transduction, and aberrant nucleocytoplasmic shuttling of MTFs is closely associated with tumor initiation, progression, and resistance to anticancer therapies. Studies have demonstrated that MTFs, such as human epidermal growth factor receptor (HER), fibroblast growth factor receptor (FGFR), β-catenin, Notch, insulin-like growth factor 1 receptor (IGF-1R), and insulin receptor (IR), play critical roles in tumorigenesis and cancer progression. Targeted therapies developed against HERs and FGFRs, among these MTFs, have yielded significant success in cancer treatment. However, the development of drug resistance remains a major challenge. As research on MTFs progress, it is anticipated that additional MTF-targeted therapies will be developed to enhance cancer treatment. In this review, we summarized recent advancements in the study of MTFs and their roles in carcinogenesis and therapy, aiming to provide valuable insights into the potential of targeting MTF pathways for the reseach of therapeutic strategies.

There has been significant improvement in treating metastatic non-small-cell lung cancer (mNSCLC) over the past 2 decades. The aim of this study is to describe the use of tyrosine kinase inhibitors (TKIs) in Qatar. This study focuses on the objective response rate (ORR) and reported adverse drug events (ADEs) of TKIs used for the management of patients with mNSCLC.

This is a descriptive retrospective cohort study. All non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations who received TKIs between 2015 and 2019 in Qatar were included. The TKIs used during this period include EGFR inhibitors such as afatinib, erlotinib, gefitinib, and osimertinib and ALK inhibitors such as alectinib and crizotinib. The response on each TKI was identified by reporting the ORR (as the sum of the complete response [CR] and the partial response [PR]), in addition stable disease (SD) and disease progression (DP) were reported. While ADEs were reported using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE).

A total of 63 patients were included, of which 36 cases (57.1%) expressed EGFR mutation, and 27 patients (42.9%) expressed ALK rearrangement. The ORR in EGFR inhibitors was as follows: osimertinib 40%, gefitinib 33%, afatinib 22%, and erlotinib 18%. However, the response to the ALK-targeted therapy was 43% with alectinib and 40% with crizotinib. A total of 112 ADEs were reported. They were distributed as 63.4% (71 of 112) with the anti-EGFR and 36.6% (41 of 112) ADEs with the ALK inhibitors. In the anti-EGFR group, the most common types of ADEs were dermatological toxicity 30%, whereas, in the anti-ALK group, gastrointestinal toxicity was the most common (29%).

The EGFR-targeted and ALK-targeted therapies appear to have acceptable clinical response rate and safety profile in our population. Close and frequent monitoring of adverse events is advised to ensure a good quality of life and prevent serious complications.

In the present, we aimed to investigate the effect of anlotinib on the potential reversal of osimertinib resistance by inhibiting the formation of epithelial-to-mesenchymal transition (EMT) and angiogenesis. In a clinical case, anlotinib reversed osimertinib resistance in Non-small cell lung cancer (NSCLC). We performed an immunohistochemical experiment on tumor tissues from three non-small cell lung cancer patients exhibiting osimertinib resistance to analyze alterations in the expression levels of EMT markers and vascular endothelial growth factor A (VEGFA) before and after osimertinib resistance. The results revealed the downregulation of E-cadherin, coupled with the upregulation of vimentin and VEGFA in tumor tissues of patients exhibiting osimertinib resistance, compared with the expression in tissues of patients before taking osimertinib. Subsequently, we established osimertinib-resistant cell lines and found that the osimertinib-resistant cells acquired the EMT features. Then, we analyzed the synergistic effects of the combination therapy to verify whether anlotinib could reverse osimertinib resistance by inhibiting EMT. The expression levels of VEGFA and micro-vessels were analyzed in the combination group in vitro. Finally, we explored the reversal of osimertinib resistance in combination with anlotinib in vivo with 20 nude mice. The combined treatment of osimertinib and anlotinib effectively prevented the metastasis of resistant cells, which also inhibited tumor growth, exerted anti-tumor activity, and ultimately reversed osimertinib resistance in mice. The co-administration of osimertinib and anlotinib demonstrated their synergistic efficacy in inhibiting EMT and angiogenesis in three NSCLC patients, ultimately reversing osimertinib resistance.

With the outbreak of the coronavirus disease 2019 (COVID-19), reductions in T-cell function and exhaustion have been observed in patients post-infection of COVID-19. T cells are key mediators of anti-infection and antitumor, and their exhaustion increases the risk of compromised immune function and elevated susceptibility to cancer. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer with high incidence and mortality. Although the survival rate after standard treatment such as surgical treatment and chemotherapy has improved, the therapeutic effect is still limited due to drug resistance, side effects, and recurrence. Recent advances in molecular biology and immunology enable the development of highly targeted therapy and immunotherapy for cancer, which has driven cancer therapies into individualized treatments and gradually entered clinicians' views for treating NSCLC. Currently, with the development of photosensitizer materials, phototherapy has been gradually applied to the treatment of NSCLC. This review provides an overview of recent advancements and limitations in different treatment strategies for NSCLC under the background of COVID-19. We discuss the latest advances in phototherapy as a promising treatment method for NSCLC. After critically examining the successes, challenges, and prospects associated with these treatment modalities, their profound prospects were portrayed.

Tyrosine kinase inhibitors (TKIs) represent a relatively large class of small-molecule inhibitors that compete with ATP for the catalytic binding site of tyrosine kinase proteins. While TKIs have demonstrated effectiveness in the treatment of multiple malignancies, including chronic myelogenous leukemia, gastrointestinal tumors, non-small cell lung cancers, and HER2-overexpressing breast cancers, as is almost always the case with anti-neoplastic agents, the development of resistance often imposes a limit on drug efficacy. One common survival response utilized by tumor cells to ensure their survival in response to different stressors, including anti-neoplastic drugs, is that of autophagy. The autophagic machinery in response to TKIs in multiple tumor models has largely been shown to be cytoprotective in nature, although there are a number of cases where autophagy has demonstrated a cytotoxic function. In this review, we provide an overview of the literature examining the role that autophagy plays in response to TKIs in different preclinical tumor model systems in an effort to determine whether autophagy suppression or modulation could be an effective adjuvant strategy to increase efficiency and/or overcome resistance to TKIs.

The present study aimed to investigate physicians' perspectives on the diagnosis and treatment decisions for patients with non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) exon 20 insertion (exon20ins) mutations in a real-world setting in China using an online questionnaire.

This study was performed via the CAPTRA-Lung collaboration between December 9, 2022 and March 6, 2023. The questionnaire was distributed digitally to physicians around China and was comprised of three sections: basic characteristics of surveyed physicians, diagnosis and treatment status of NSCLC patients with the EGFR exon20ins-mutation, and physicians' perspectives on treatment options. Physicians who treat more than 10 patients with advanced NSCLC every month and who have treated patients with advanced EGFR exon20ins-mutant NSCLC in the past six months were involved in this study.

A total of 53,729 questionnaires were distributed and 390 valid ones were collected. The EGFR mutation test was performed in 80.9% and 59.9% of patients receiving first-line or second-line therapy and beyond (hereinafter "second-line")therapy, respectively. In terms of treatment options, chemotherapy plus antiangiogenic therapy was the most common treatment option (30.0% of patients in first-line settings; 25.0% of patients in second-line settings), and a certain proportion of patients received novel EGFR exon20ins-targeted agents (including tyrosine kinase inhibitors [TKIs] and bispecific antibodies) in first- or second-line settings, which accounted for 11.9% and 15.7% of all treated patients, respectively. Additionally, physicians reported the highest satisfaction score for the efficacy and safety of targeted agents. Most physicians believed that EGFR exon20ins-targeted TKIs represented the most promising treatment option (80.2% in first-line treatment and 73.3% in second-line treatment). Among several novel agents under study, sunvozertinib has received the highest recognition for efficacy and safety.

This study investigated the current diagnosis and treatment status and physicians' perspective, of patients with EGFR exon20ins-mutant NSCLC. The results highlight significant unmet clinical needs in this subgroup of patients. EGFR exon20ins-targeted TKIs were recognized as the most promising treatment regimen and may benefit more patients considering their awareness and acceptance of targeted therapy.

Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has shown significant clinical benefits in patients with EGFR-sensitizing mutations or the EGFR T790M mutation. The homologous recombination (HR) pathway is crucial for repairing DNA double-strand breaks (DSBs). Rad51 plays a central role in HR, facilitating the search for homology and promoting DNA strand exchange between homologous DNA molecules. Rad51 is overexpressed in numerous types of cancer cells. B02, a specific small molecule inhibitor of Rad51, inhibits the DNA strand exchange activity of Rad51. Previous studies have indicated that B02 disrupted Rad51 foci formation in response to DNA damage and inhibited DSBs repair in human cells and sensitized them to chemotherapeutic drugs in vitro and in vivo. However, the potential therapeutic effects of combining osimertinib with a Rad51 inhibitor are not well understood. The aim of this study was to elucidate whether the downregulation of Rad51 expression and activity can enhance the osimertinib-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells.

We used the MTS, trypan blue dye exclusion and colony-formation ability assay to determine whether osimertinib alone or in combination with B02 had cytotoxic effects on NSCLC cell lines. Real-time polymerase chain reaction was conducted to measure the amounts of Rad51 mRNA. The protein levels of phosphorylated AKT and Rad51 were determined by Western blot analysis.

We found that osimertinib reduced Rad51 expression by inactivating AKT activity. Rad51 knockdown using small interfering RNA or AKT inactivation through the phosphatidylinositol 3-kinase inhibitor LY294002 or si-AKT RNA transfection enhanced the cytotoxic and growth inhibitory effects of osimertinib. In contrast, AKT-CA (a constitutively active form of AKT) vector-enforced expression could mitigate the cytotoxic and cell growth inhibitory effects of osimertinib. Furthermore, B02 significantly enhanced the cytotoxic and cell growth inhibitory effects of osimertinib in NSCLC cells. Compared to parental cells, the activation of AKT and Rad51 expression in osimertinib-resistant cells could not be significantly inhibited by osimertinib treatment. Moreover, the increased expression of Rad51 is associated with the resistance mechanism in osimertinib-resistant H1975 and A549 cells.

Collectively, the downregulation of Rad51 expression and activity enhances the cytotoxic effect of osimertinib in human NSCLC cells.

Combining pemetrexed with bevacizumab may have some potential in improving the efficacy in patients with non-small-cell lung cancer (NSCLC), and this meta-analysis aims to explore the impact of pemetrexed addition to bevacizumab on treatment efficacy for NSCLC.

PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched, and we included randomized controlled trials (RCTs) assessing the effect of pemetrexed addition to bevacizumab on treatment efficacy in patients with NSCLC. Overall survival and progression-free survival were included in this meta-analysis.

Four RCTs were finally included in the meta-analysis. Overall, compared with bevacizumab for NSCLC, pemetrexed addition showed significantly improved overall survival (hazard ratio [HR] = 0.87; 95% confidence interval [CI] = 0.76 to 0.99; P = 0.03), survival rate (odd ratio [OR] = 1.41; 95% CI = 1.06 to 1.86; P = 0.02), progression-free survival (HR = 0.63; 95% CI = 0.55 to 0.72; P < 0.00001) and progression-free survival rate (OR = 1.92; 95% CI = 1.38 to 2.67; P < 0.00001), but led to the increase in grade ≥ 3 adverse events (OR = 2.15; 95% CI = 1.62 to 2.84; P < 0.00001).

Pemetrexed addition may be effective to improve treatment efficacy for NSCLC compared to bevacizumab treatment.

Drug-induced liver injury (DILI) is one of the most frequently adverse reactions in clinical drug use, usually caused by drugs or herbal compounds. Compared with other populations, cancer patients are more prone to abnormal liver function due to primary or secondary liver malignant tumor, radiation-induced liver injury and other reasons, making potential adverse reactions from liver damage caused by anticancer drugs of particular concernduring clinical treatment process. In recent years, the application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has changed the treatment status of a series of solid malignant tumors. Unfortunately, the increasing incidence of hepatotoxicitylimits the clinical application of EGFR-TKIs. The mechanisms of liver injury caused by EGFR-TKIs were complex. Despite more than a decade of research, other than direct damage to hepatocytes caused by inhibition of cellular DNA synthesis and resulting in hepatocyte necrosis, the rest of the specific mechanisms remain unclear, and few effective solutions are available. This review focuses on the clinical feature, incidence rates and the recent advances on the discovery of mechanism of hepatotoxicity in EGFR-TKIs, as well as rechallenge and therapeutic strategies underlying hepatotoxicity of EGFR-TKIs.

Exosomes are small lipid nanovesicles with a diameter of 30-150 nm. They are present in all body fluids and are actively secreted by the majority of cells through the process of exocytosis. Exosomes play an essential role in intercellular communication and act as significant molecular carriers in regulating various physiological and pathological processes, such as the emergence of drug resistance in tumors. Tumor-associated exosomes transfer drug resistance to other tumor cells by releasing substances such as multidrug resistance proteins and miRNAs through exosomes. These substances change the cell phenotype, making it resistant to drugs. Tumor-associated exosomes also play a role in impacting drug resistance in other cells, like immune cells and stromal cells. Exosomes alter the behavior and function of these cells to help tumor cells evade immune surveillance and form a tumor niche. In addition, exosomes also export substances such as tumoricidal drugs and neutralizing antibody drugs to help tumor cells resist drug therapy. In this review, we summarize the mechanisms of exosomes in promoting drug resistance by delivering cargo in the context of the tumor microenvironment (TME).

The aim of this study is to assess the impact of serum magnesium (Mg) levels on prognostic outcomes in patients with non-small cell lung cancer (NSCLC) undergoing treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). A cohort comprising 91 patients with NSCLC with epidermal growth factor receptor mutations received EGFR-TKI therapy. Assessments of liver and kidney function and electrolyte levels were conducted before treatment initiation and after completing two cycles of EGFR-TKI therapy. Data on variables such as age, gender, presence of distant metastasis, smoking history, other therapeutic interventions, and the specific TKI used were collected for analysis. Cox regression analysis revealed that patients with higher Mg levels prior to EGFR-TKI therapy had significantly longer progression-free survival (PFS) and overall survival (OS). Elevated Mg levels remained predictive of PFS and OS after two cycles of EGFR-TKI therapy. Multiple regression analysis confirmed these findings. Additionally, it was observed that smokers might represent a unique population, demonstrating a correlation between OS and Mg levels. Our findings indicate that serum Mg level is a prognostic factor in patients with NSCLC undergoing EGFR-TKI therapy. This may provide new insights into the underlying mechanisms of EGFR-TKI therapy related to electrolyte balance.

Cytokines are critical in regulating immune responses and cellular behavior, playing dual roles in both normal physiology and the pathology of diseases such as cancer. These molecules, including interleukins, interferons, tumor necrosis factors, chemokines, and growth factors like TGF-β, VEGF, and EGF, can promote or inhibit tumor growth, influence the tumor microenvironment, and impact the efficacy of cancer treatments. Recent advances in targeting these pathways have shown promising therapeutic potential, offering new strategies to modulate the immune system, inhibit tumor progression, and overcome resistance to conventional therapies. In this review, we summarized the current understanding and therapeutic implications of targeting cytokine and chemokine signaling pathways in cancer. By exploring the roles of these molecules in tumor biology and the immune response, we highlighted the development of novel therapeutic agents aimed at modulating these pathways to combat cancer. The review elaborated on the dual nature of cytokines as both promoters and suppressors of tumorigenesis, depending on the context, and discussed the challenges and opportunities this presents for therapeutic intervention. We also examined the latest advancements in targeted therapies, including monoclonal antibodies, bispecific antibodies, receptor inhibitors, fusion proteins, engineered cytokine variants, and their impact on tumor growth, metastasis, and the tumor microenvironment. Additionally, we evaluated the potential of combining these targeted therapies with other treatment modalities to overcome resistance and improve patient outcomes. Besides, we also focused on the ongoing research and clinical trials that are pivotal in advancing our understanding and application of cytokine- and chemokine-targeted therapies for cancer patients.

The USFDA granted regular approval to Osimertinib (AZD9291) on March 2017, for treating individuals with metastatic Non-Small Cell Lung Cancer having EGFR T790M mutation. Clinically, Osimertinib stands at the forefront for the treatment of patients with Non-Small Cell Lung Cancer. Osimertinib forms a covalent bond with the Cys797 residue and predominantly spares binding to WT-EGFR, thereby reducing toxicity and enabling the administration of doses that effectively inhibit T790M. However, a high percentage of patients treated with Osimertinib (AZD9291) developed a tertiary cysteine797 to serine797 (C797S) mutation in the EGFR kinase domain, rendering resistance to it. This comprehensive review sheds light on the chemistry, computational aspects, structural features, and expansive spectrum of biological activities of Osimertinib and its analogues. The in-depth exploration of these facets serves as a valuable resource for medicinal chemists, empowering them to design better Osimertinib analogues. This exhaustive study not only provides insights into improving potency but also emphasizes considerations for mutant selectivity and optimizing pharmacokinetic properties. This review acts as a guiding beacon for the strategic design and development of next-generation Osimertinib analogues.

Lung cancer remains the leading cause of mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer with a generally poor prognosis. In recent years, advances in targeted therapy and sequencing technology have brought significant improvement in the therapeutic outcomes of patients with advanced NSCLC. Targeted inhibitors directed against specific mutated or rearranged oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and receptor tyrosine kinase ROS proto-oncogene 1(ROS1) among others, exhibit promising anti-tumor activity. Unfortunately, some patients develop acquired resistance and disease progression soon after initial remission. Despite the continuous development of new drugs and strategies to overcome drug resistance, it is still a major challenge in the treatment of NSCLC. The landscape of targeted therapy for NSCLC is evolving rapidly in response to the pace of scientific research. This study aimed to provide a comprehensive review of tumor target antigens and agents related to targeted therapy in NSCLC.

Non-small cell lung cancer (NSCLC) remains an unsolved challenge in oncology, signifying a substantial global health burden. While considerable progress has been made in recent years through the emergence of immunotherapy modalities, such as immune checkpoint inhibitors (ICIs), monotherapies often yield limited clinical outcomes. The rationale behind combining various immunotherapeutic or other anticancer agents, the mechanistic underpinnings, and the clinical evidence supporting their utilization is crucial in NSCLC therapy. Regarding the synergistic potential of combination immunotherapies, this study aims to provide insights to help the landscape of NSCLC treatment and improve clinical outcomes. In addition, this review article discusses the challenges and considerations of combination regimens, including toxicity management and patient selection.

The treatment of advanced non-small cell lung cancer (NSCLC) harboring an oncogenic epidermal growth factor receptor mutation (EGFRm) is currently based on osimertinib, a third-generation tyrosine kinase inhibitor (TKI). High Programmed death ligand 1 (PD-L1) expression ≥ 50% demonstrated to be a negative prognostic factor, mostly among Asian populations treated with 1st/2nd generation TKI.

We investigated the impact of PD-L1 expression on the progression free survival (PFS) and overall survival (OS) within a cohort of patients receiving osimertinib as first-line treatment.

Our bi-centre French retrospective study included all newly diagnosed patients with an advanced EGFRm (common and uncommon) NSCLC, between May 2018 and November 2022, treated with osimertinib. The primary endpoint was OS according to tumor proportion score PD-L1 expression (low/intermediate < 50% vs high ≥ 50%). Survival analyses were performed using Kaplan-Meier method and Cox model for adjusted multivariate analysis.

Of 96 patients, median age was 71 (IQR 62-76), 70 were women (72.9%), 81 had a performance status (PS) 0-1 (84.3%). Median follow-up was 22.6 months (95% CI 20.5-24.7). Twenty patients (20.8%) had high PD-L1 expression ≥ 50%. No significant differences in baseline characteristics were observed based on PD-L1 status. Patients with PD-L1 ≥ 50% had significant shorter PFS and OS than those with PD-L1 < 50%, respectively 9.3 vs 17.5 months (p = 0.044 months) and 14.3 vs 26.0 months (p = 0.025). Multivariable adjustment for baseline characteristics found that PS ≥ 2 (HR 2.79, 95% CI 1.12-6.93, p = 0.027), PD-L1 ≥ 50% (HR 2.61, 95% CI 1.31 to 5.22, p = 0.007) and uncommon EGFR mutation (HR 4.59, 95% CI 1.95-10.80, p = <0.001) were associated with a shorter OS. Brain metastases at diagnosis and age ≥ 65 were not, respectively HR 1.66 (95% CI 0.90-3.06, p = 0.11) and HR 0.95 (95% CI 0.50-1.80, p=0.9).

Our study found that PD-L1 expression ≥ 50% was associated with a shorter OS in EGFRm NSCLC patients treated with first line osimertinib. Further research is warranted to understand the underlying molecular and cellular mechanisms of this correlation.

The advent of targeted drug therapy has greatly changed the treatment landscape of advanced non-small cell lung cancer(NSCLC), but the cardioxic side effects of targeted drug anti-cancer therapy seriously affect the prognosis of NSCLC, and it has become the second leading cause of death in cancer patients. Therefore, early identification of the cardiotoxic side effects of targeted drugs is crucial for the prevention and treatment of cardiovascular diseases. The cardiotoxic side effects that may be caused by novel targeted drugs epidermal growth factor receptor inhibitors, including thromboembolic events, heart failure, cardiomyopathy, arrhythmia and hypertension, are discussed, and the mechanisms of their respective adverse cardiovascular reactions are summarized, to provide useful recommendations for cardiac management of patients with advanced lung cancer to maximize treatment outcomes for lung cancer survivors. Clinicians need to balance the risk-benefit ratio between targeted therapy for malignant tumors and drug-induced cardiotoxicity, and evaluate and monitor TKIs-induced cardiotoxicity through electrocardiogram, cardiac imaging, biomarkers, etc., so as to remove the susceptibility risk factors as soon as possible and provide a reference for the clinical use of such drugs in the treatment of malignant tumors.

The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) is a recognized resistance mechanism and a hindrance to therapies using epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The paucity of pretranslational/posttranslational clinical samples limits the deeper understanding of resistance mechanisms and the exploration of effective therapeutic strategies. Here, we developed preclinical neuroendocrine (NE) transformation models. Next, we identified a transcriptional reprogramming mechanism that drives resistance to erlotinib in NE transformation cell lines and cell-derived xenograft mice. We observed the enhanced expression of genes involved in the EHMT2 and WNT/β-catenin pathways. In addition, we demonstrated that EHMT2 increases methylation of the SFRP1 promoter region to reduce SFRP1 expression, followed by activation of the WNT/β-catenin pathway and TKI-mediated NE transformation. Notably, the similar expression alterations of EHMT2 and SFRP1 were observed in transformed SCLC samples obtained from clinical patients. Importantly, suppression of EHMT2 with selective inhibitors restored the sensitivity of NE transformation cell lines to erlotinib and delayed resistance in cell-derived xenograft mice. We identify a transcriptional reprogramming process in NE transformation and provide a potential therapeutic target for overcoming resistance to erlotinib.