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Scientific Reports May 2024Capmatinib is a potent selective mesenchymal-epithelial transition inhibitor approved in 2020 for the treatment of metastatic non-small cell lung cancer. As real-world...
Capmatinib is a potent selective mesenchymal-epithelial transition inhibitor approved in 2020 for the treatment of metastatic non-small cell lung cancer. As real-world evidence is very limited, this study evaluated capmatinib-induced adverse events through data mining of the FDA Adverse Event Reporting System database. Four disproportionality analysis methods were employed to quantify the signals of capmatinib-related adverse events. The difference in capmatinib-associated adverse event signals was further investigated with respect to sex, age, weight, dose, onset time, continent, and concomitant drug. A total of 1518 reports and 4278 adverse events induced by capmatinib were identified. New significant adverse event signals emerged, such as dysphagia, dehydration, deafness, vocal cord paralysis, muscle disorder, and oesophageal stenosis. Notably, higher risk of alanine aminotransferase and aspartate aminotransferase increases were observed in females, especially when capmatinib was combined with immune checkpoint inhibitors. Compared with Europeans and Asians, Americans were more likely to experience peripheral swelling, especially in people > 65 years of age. Renal impairment and increased blood creatinine were more likely to occur with single doses above 400 mg and in Asians. This study improves the understanding of safety profile of capmatinib.
Topics: Humans; Male; Female; United States; Middle Aged; Aged; United States Food and Drug Administration; Pharmacovigilance; Adverse Drug Reaction Reporting Systems; Benzamides; Adult; Triazines; Carcinoma, Non-Small-Cell Lung; Aged, 80 and over; Young Adult; Lung Neoplasms; Adolescent; Imidazoles
PubMed: 38762672
DOI: 10.1038/s41598-024-62356-w -
Nature Communications May 2024Cysteine metabolism occurs across cellular compartments to support diverse biological functions and prevent the induction of ferroptosis. Though the disruption of...
Cysteine metabolism occurs across cellular compartments to support diverse biological functions and prevent the induction of ferroptosis. Though the disruption of cytosolic cysteine metabolism is implicated in this form of cell death, it is unknown whether the substantial cysteine metabolism resident within the mitochondria is similarly pertinent to ferroptosis. Here, we show that despite the rapid depletion of intracellular cysteine upon loss of extracellular cystine, cysteine-dependent synthesis of Fe-S clusters persists in the mitochondria of lung cancer cells. This promotes a retention of respiratory function and a maintenance of the mitochondrial redox state. Under these limiting conditions, we find that glutathione catabolism by CHAC1 supports the mitochondrial cysteine pool to sustain the function of the Fe-S proteins critical to oxidative metabolism. We find that disrupting Fe-S cluster synthesis under cysteine restriction protects against the induction of ferroptosis, suggesting that the preservation of mitochondrial function is antagonistic to survival under starved conditions. Overall, our findings implicate mitochondrial cysteine metabolism in the induction of ferroptosis and reveal a mechanism of mitochondrial resilience in response to nutrient stress.
Topics: Humans; Cysteine; Mitochondria; Glutathione; Ferroptosis; Lung Neoplasms; Cell Line, Tumor; Carcinoma, Non-Small-Cell Lung; Iron-Sulfur Proteins; Oxidation-Reduction; Mice
PubMed: 38762605
DOI: 10.1038/s41467-024-48695-2 -
Journal of Cellular and Molecular... May 2024Smoking is a well-known risk factor for non-small-cell lung cancer (NSCLC) and bladder urothelial carcinoma (BLCA). Despite this, there has been no investigation into a...
Smoking is a well-known risk factor for non-small-cell lung cancer (NSCLC) and bladder urothelial carcinoma (BLCA). Despite this, there has been no investigation into a prognostic marker based on smoking-related genes that could universally predict prognosis in these cancers and correlate with immune checkpoint therapy. This study aimed to identify smoking-related differential genes in NSCLC and BLCA, analyse their roles in patient prognosis and immune checkpoint therapy through subgroup analyses, and shed light on PRR11 as a crucial prognostic gene in both cancers. By examining PRR11 co-expressed genes, a prognostic model was constructed and its impact on immunotherapy for NSCLC and BLCA was evaluated. Molecular docking and tissue microarray analyses were conducted to explore the correlation between PRR11 and its reciprocal gene SPDL1. Additionally, miRNAs associated with PRR11 were analysed. The study confirmed a strong link between smoking-related genes, prognosis, and immune checkpoint therapy in NSCLC and BLCA. PRR11 was identified as a key smoking-associated gene that influences the efficacy of immune checkpoint therapy by modulating the stemness of these cancers. A prognostic model based on PRR11 co-expressed genes in BLCA was established and its prognostic value was validated in NSCLC. Furthermore, it was found that PRR11 regulates PDL1 via SPDL1, impacting immunotherapeutic efficacy in both cancers. The involvement of hsa-miR-200b-3p in the regulation of SPDL1 expression by PRR11 was also highlighted. Overall, the study elucidates that PRR11 modulates patient immunotherapy by influencing PDL1 expression through its interaction with SPDL1, with potential upstream regulation by hsa-miR-200b-3p.
Topics: Humans; Urinary Bladder Neoplasms; Lung Neoplasms; Prognosis; Smoking; Gene Expression Regulation, Neoplastic; Immunotherapy; MicroRNAs; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Male; Female
PubMed: 38760964
DOI: 10.1111/jcmm.18384 -
Communications Biology May 2024STAT3 is constitutively activated in many cancer types, including lung cancer, and can induce cancer cell proliferation and cancer stem cell (CSC) maintenance. STAT3 is...
STAT3 is constitutively activated in many cancer types, including lung cancer, and can induce cancer cell proliferation and cancer stem cell (CSC) maintenance. STAT3 is activated by tyrosine kinases, such as JAK and SRC, but the mechanism by which STAT3 maintains its activated state in cancer cells remains unclear. Here, we show that PRMT5 directly methylates STAT3 and enhances its activated tyrosine phosphorylation in non-small cell lung cancer (NSCLC) cells. PRMT5 expression is also induced by STAT3, suggesting the presence of a positive feedback loop in cancer cells. Furthermore, methylation of STAT3 at arginine 609 by PRMT5 is important for its transcriptional activity and support of tumour growth and CSC maintenance. Indeed, NSCLC cells expressing the STAT3 mutant which R609 was replaced to alanine (R609K) show significantly impaired tumour growth in nude mice. Overall, our study reveals a mechanism by which STAT3 remains activated in NSCLC and provides a new target for cancer therapeutic approaches.
Topics: STAT3 Transcription Factor; Protein-Arginine N-Methyltransferases; Humans; Lung Neoplasms; Neoplastic Stem Cells; Animals; Mice; Carcinoma, Non-Small-Cell Lung; Methylation; Cell Proliferation; Mice, Nude; Cell Line, Tumor; Phosphorylation; Gene Expression Regulation, Neoplastic
PubMed: 38760429
DOI: 10.1038/s42003-024-06290-7 -
Nature Communications May 2024Osimertinib (Osi) is a widely used epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). However, the emergence of resistance is inevitable, partly due...
Osimertinib (Osi) is a widely used epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). However, the emergence of resistance is inevitable, partly due to the gradual evolution of adaptive resistant cells during initial treatment. Here, we find that Osi treatment rapidly triggers adaptive resistance in tumor cells. Metabolomics analysis reveals a significant enhancement of oxidative phosphorylation (OXPHOS) in Osi adaptive-resistant cells. Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA4-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Lung Neoplasms; Acrylamides; Protein Kinase Inhibitors; Cell Line, Tumor; Ferritins; Aniline Compounds; Nuclear Receptor Coactivators; Oxidative Phosphorylation; Animals; Mice; Copper; Autophagy; Mice, Nude; Tyrosine Kinase Inhibitors; Indoles; Pyrimidines
PubMed: 38760351
DOI: 10.1038/s41467-024-48433-8 -
Medicine May 2024To explore the potential mechanism of Chai Gui Zexie Decoction for non-small cell lung cancer (NSCLC) treatment using network pharmacology, bioinformatics, and molecular... (Observational Study)
Observational Study
To explore the potential mechanism of Chai Gui Zexie Decoction for non-small cell lung cancer (NSCLC) treatment using network pharmacology, bioinformatics, and molecular docking. The active ingredients of Chai Gui Zexie Decoction and the associated predicted targets were screened using the TCMSP database. NSCLC-related targets were obtained from GeneCards and OMIM. Potential action targets, which are intersecting drug-predicted targets and disease targets, were obtained from Venny 2.1. The protein-protein interaction network was constructed by importing potential action targets into the STRING database, and the core action targets and core ingredients were obtained via topological analysis. The core action targets were entered into the Metascape database, and Gene Ontology annotation analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were performed. Differentially expressed genes were screened using the Gene Expression Omnibus, and the key targets were obtained by validating the core action targets. The key targets were input into The Tumor IMmune Estimation Resource for immune cell infiltration analysis. Finally, the molecular docking of key targets and core ingredients was performed. We obtained 60 active ingredients, 251 drug prediction targets, and 2133 NSCLC-related targets. Meanwhile, 147 potential action targets were obtained, and 47 core action targets and 40 core ingredients were obtained via topological analysis. We detected 175 pathways related to NSCLC pharmaceutical therapy. In total, 1249 Gene Ontology items were evaluated. Additionally, 3102 differential genes were screened, and tumor protein P53, Jun proto-oncogene, interleukin-6, and mitogen-activated protein kinase 3 were identified as the key targets. The expression of these key targets in NSCLC was correlated with macrophage, CD4+ T, CD8+ T, dendritic cell, and neutrophil infiltration. The molecular docking results revealed that the core ingredients have a potent affinity for the key targets. Chai Gui Zexie Decoction might exert its therapeutic effect on NSCLC through multiple ingredients, targets, and signaling pathways.
Topics: Carcinoma, Non-Small-Cell Lung; Molecular Docking Simulation; Humans; Drugs, Chinese Herbal; Lung Neoplasms; Computational Biology; Network Pharmacology; Protein Interaction Maps; Proto-Oncogene Mas; Gene Ontology
PubMed: 38758858
DOI: 10.1097/MD.0000000000038204 -
PloS One 2024Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we...
Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma.
Topics: Humans; Plasminogen Activator Inhibitor 1; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Proto-Oncogene Proteins c-met; Crizotinib; Lung Neoplasms; Cell Line, Tumor; Protein Kinase Inhibitors; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic
PubMed: 38758826
DOI: 10.1371/journal.pone.0300644 -
Cancer Immunology, Immunotherapy : CII May 2024Effective treatment after EGFR-TKI resistance is of great clinical concern. We aimed to investigate the efficacy and safety of anlotinib in combination with an...
The later-line efficacy and safety of immune checkpoint inhibitors plus anlotinib in EGFR-mutant patients with EGFR-TKI-resistant NSCLC: a single-center retrospective study.
BACKGROUND
Effective treatment after EGFR-TKI resistance is of great clinical concern. We aimed to investigate the efficacy and safety of anlotinib in combination with an anti-PD-1/PD-L1 antibody in later-line therapy for EGFR-mutant NSCLC patients after TKI treatment failure and to explore the independent predictive factors of therapeutic efficacy.
METHODS
A total of 71 patients with confirmed advanced EGFR-mutated NSCLC who progressed after previous standard EGFR-TKI therapy but still failed after multiline treatments were included retrospectively in this study. Most of the patients had previously received at least three lines of treatment. All were treated with anlotinib combined with anti-PD-1 or anti-PD-L1 therapy. The safety of this combined treatment was assessed by the incidence of adverse events. The efficacy of the regimens was evaluated by survival analysis (OS, PFS, ORR, DCR).
RESULTS
The median follow-up period was 28.6 months (range: 2.3-54.0 months), and the median number of treatment lines was 4. The overall response rate (ORR) and disease control rate (DCR) were 19.7% and 77.5%, respectively. The median PFS was 5.8 months (95% CI 4.2-7.4 months), and the median OS was 17.1 months (95% CI 12.0-22.3 months). Patients who received immune checkpoint inhibitors plus anlotinib had an encouraging intracranial ORR of 38.5% and a DCR of 80.8%. ECOG performance status < 2 at baseline was independent protective factors of PFS. Metastatic organs and ECOG performance status were independent parameters in predicting OS. Treatment-related adverse events occurred in 66 (93.0%) patients; most of the adverse events were Grade 1-2, and no increase in adverse events was observed compared to monotherapy.
CONCLUSION
Anlotinib combined with an anti-PD-1/PD-L1-based regimen exhibited promising efficacy and tolerance in NSCLC patients with EGFR mutations after previous TKI failure. The efficacy of this combined regimen in patients with EGFR mutations should be further evaluated.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Male; Female; Retrospective Studies; Indoles; Quinolines; Middle Aged; Immune Checkpoint Inhibitors; Lung Neoplasms; Aged; Protein Kinase Inhibitors; ErbB Receptors; Mutation; Adult; Drug Resistance, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Aged, 80 and over
PubMed: 38758372
DOI: 10.1007/s00262-024-03712-7 -
International Journal of Oncology Jun 2024Ferroptosis, a recently discovered type of programmed cell death triggered by excessive accumulation of iron‑dependent lipid peroxidation, is linked to several...
Long non‑coding RNA lung cancer‑associated transcript 1 regulates ferroptosis via microRNA‑34a‑5p‑mediated GTP cyclohydrolase 1 downregulation in lung cancer cells.
Ferroptosis, a recently discovered type of programmed cell death triggered by excessive accumulation of iron‑dependent lipid peroxidation, is linked to several malignancies, including non‑small cell lung cancer. Long non‑coding RNAs (lncRNAs) are involved in ferroptosis; however, data on their role and mechanism in cancer therapy remains limited. Therefore, the aim of the present study was to identify ferroptosis‑associated mRNAs and lncRNAs in A549 lung cancer cells treated with RAS‑selective lethal 3 (RSL3) and ferrostatin‑1 (Fer‑1) using RNA sequencing. The results demonstrated that lncRNA lung cancer‑associated transcript 1 (LUCAT1) was significantly upregulated in lung adenocarcinoma and lung squamous cell carcinoma tissues. Co‑expression analysis of differentially expressed mRNAs and lncRNAs suggested that LUCAT1 has a crucial role in ferroptosis. LUCAT1 expression was markedly elevated in A549 cells treated with RSL3, which was prevented by co‑incubation with Fer‑1. Functionally, overexpression of LUCAT1 facilitated cell proliferation and reduced the occurrence of ferroptosis induced by RSL3 and Erastin, while inhibition of LUCAT1 expression reduced cell proliferation and increased ferroptosis. Mechanistically, downregulation of LUCAT1 resulted in the downregulation of both GTP cyclohydrolase 1 (GCH1) and ferroptosis suppressor protein 1 (FSP1). Furthermore, inhibition of LUCAT1 expression upregulated microRNA (miR)‑34a‑5p and then downregulated GCH1. These results indicated that inhibition of LUCAT1 expression promoted ferroptosis by modulating the downregulation of GCH1, mediated by miR‑34a‑5p. Therefore, the combination of knocking down LUCAT1 expression with ferroptosis inducers may be a promising strategy for lung cancer treatment.
Topics: Humans; Ferroptosis; MicroRNAs; Lung Neoplasms; RNA, Long Noncoding; Gene Expression Regulation, Neoplastic; Down-Regulation; A549 Cells; GTP Cyclohydrolase; Cell Proliferation; Carcinoma, Non-Small-Cell Lung; Male; Cell Line, Tumor; Female; Adenocarcinoma of Lung
PubMed: 38757341
DOI: 10.3892/ijo.2024.5652 -
Frontiers in Immunology 2024Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small-cell lung cancer (NSCLC), which is resistant to chemotherapy and radiotherapy with a poor prognosis....
BACKGROUND
Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small-cell lung cancer (NSCLC), which is resistant to chemotherapy and radiotherapy with a poor prognosis. PSC is highly malignant and is prone to recurrence even after surgery. The programmed death-ligand 1 (PD-L1) tumor cell proportion score (TPS) 5%, TERT and TP53 gene mutations were detected in this patient accompanied by multiple metastatic sites. The anlotinib is a novel multitarget tyrosine kinase inhibitor (TKI) that could be effective for advanced NSCLC and some sarcoma patients. Limited clinical trials and case reports have shown that PSC patients with gene mutations and PD-L1 expression have good responses to multitarget antiangiogenic drug and immune checkpoint inhibitors (ICIs). In this article, we reported a case with metastatic PSC diagnosed by Computed Tomography (CT)-guided needle biopsy treated with immunotherapy combined with antiangiogenic drugs as a neoadjuvant chemotherapy (NACT). PSC is controlled and the patient achieves successfully limb salvage treatment by surgical resection. Therefore, targeted therapy and immunotherapy can provide sufficient surgical opportunities for limb salvage in the treatment of metastatic PSC patients.
CASE SUMMARY
A 69-year-old male diagnosed with malignant bone tumor in the proximal femur was admitted to our hospital in June 2022 with recurrent fever as well as swelling and pain in the left thigh for twenty days. The initial computed tomography (CT) scan of the chest showed a pulmonary cavity (20 mm × 30 mm) and scattered lung masses. Subsequently, he underwent a CT-guided needle biopsy to distinguish the essence of osteolytic bone destruction and soft tissue mass in the left proximal femur which showed metastatic sarcomatoid carcinoma histology. Genetic testing revealed TERT c.-124C mutation (abundance 8.81%), TP53 p.R342 mutation (abundance 11.35%), tumor mutational burden (TMB) 7.09 muts/Mb, microsatellite stability (MSS), and PD-L1 (SP263) TPS 5% were also detected. The patient was tentatively treated with a combination of antiangiogenic drug and PD-1 inhibitor. After one course, the tumor volume significantly reduced in magnetic resonance imaging (MRI) and pathological fracture occurred in the femur after combined treatment. The patient received proximal femoral tumor resection and prosthesis replacement after defervescence. Sequentially sintilimab with anlotinib were administered for over 1 year. Finally, the local tumor was well controlled, and no obvious drug-related adverse reactions were observed. The lesions in the lung remained in partial response (PR) for more than 16 months and complete response (CR) of metastatic tumor in the proximal femur was observed through imaging examinations.
CONCLUSION
This is the first reported case of a metastatic PSC in femur showing a favorable response to the treatment consisting of anlotinib combined with sintilimab. This case suggests that antiangiogenic therapy combined with immunotherapy may benefit patients with metastatic PSC in the preoperative adjuvant therapy for limb salvage.
Topics: Humans; Antibodies, Monoclonal, Humanized; Bone Neoplasms; Lung Neoplasms; Quinolines; Neoadjuvant Therapy; Male; Indoles; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Aged; Treatment Outcome; Immune Checkpoint Inhibitors
PubMed: 38756778
DOI: 10.3389/fimmu.2024.1372279