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Zhongguo Fei Ai Za Zhi = Chinese... May 2024Lung cancer is the most common malignant disease and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung... (Review)
Review
Lung cancer is the most common malignant disease and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung cancers, and the probability of NSCLC gene mutations is high, with a wide variety of types. With the development of next-generation sequencing (NGS) detection technology, more and more patients with rare fusion gene mutations are detected. Neuregulin 1 (NRG1) gene is a rare oncogenic driver that can lead to activation of human epidermal growth factor receptor 3 (Her3/ErbB3) mediated pathway, resulting in tumor formation. In this article, we reported a case of mixed NSCLC with CRISPLD2-NRG1 fusion detected by RNA-based NGS, who responsed to Afatinib well after 1 month of treatment, and magnetic resonance imaging (MRI) showed shrinkage of intracranial lesions. Meanwhile, we also compiled previously reported NSCLC patients with NRG1 rare gene fusion mutation, in order to provide effective references for clinical diagnosis and treatment. .
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Neuregulin-1; Afatinib; Oncogene Proteins, Fusion; Middle Aged; Male; Cell Adhesion Molecules; Female
PubMed: 38880928
DOI: 10.3779/j.issn.1009-3419.2024.102.19 -
Scientific Reports Feb 2024Disulfidptosis a new cell death mode, which can cause the death of Hepatocellular Carcinoma (HCC) cells. However, the significance of disulfidptosis-related Long...
Disulfidptosis a new cell death mode, which can cause the death of Hepatocellular Carcinoma (HCC) cells. However, the significance of disulfidptosis-related Long non-coding RNAs (DRLs) in the prognosis and immunotherapy of HCC remains unclear. Based on The Cancer Genome Atlas (TCGA) database, we used Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression model to construct DRL Prognostic Signature (DRLPS)-based risk scores and performed Gene Expression Omnibus outside validation. Survival analysis was performed and a nomogram was constructed. Moreover, we performed functional enrichment annotation, immune infiltration and drug sensitivity analyses. Five DRLs (AL590705.3, AC072054.1, AC069307.1, AC107959.3 and ZNF232-AS1) were identified to construct prognostic signature. DRLPS-based risk scores exhibited better predictive efficacy of survival than conventional clinical features. The nomogram showed high congruence between the predicted survival and observed survival. Gene set were mainly enriched in cell proliferation, differentiation and growth function related pathways. Immune cell infiltration in the low-risk group was significantly higher than that in the high-risk group. Additionally, the high-risk group exhibited higher sensitivity to Afatinib, Fulvestrant, Gefitinib, Osimertinib, Sapitinib, and Taselisib. In conclusion, our study highlighted the potential utility of the constructed DRLPS in the prognosis prediction of HCC patients, which demonstrated promising clinical application value.
Topics: Humans; Carcinoma, Hepatocellular; RNA, Long Noncoding; Liver Neoplasms; Prognosis; Nomograms
PubMed: 38388539
DOI: 10.1038/s41598-024-54115-8 -
Frontiers in Pharmacology 2023The immune-related lncRNAs (IRLs) are critical for the development of cervical cancer (CC), but it is still unclear how exactly ILRs contribute to CC. In this study, we...
The construction of a prognostic model of cervical cancer based on four immune-related LncRNAs and an exploration of the correlations between the model and oxidative stress.
The immune-related lncRNAs (IRLs) are critical for the development of cervical cancer (CC), but it is still unclear how exactly ILRs contribute to CC. In this study, we aimed to examine the relationship between IRL and CC in detail. First, the RNAseq data and clinical data of CC patients were collected from The Cancer Genome Atlas (TCGA) database, along with the immune genes from the Import database. We used univariate cox and least absolute shrinkage and selection operator (lasso) to obtain IRLs for prediction after screening the variables. According to the expression levels and risk coefficients of IRLs, the riskscore were calculated. We analyzed the relationship between the model and oxidative stress. We stratified the risk model into two as the high and low-risk groups. We also evaluated the survival differences, immune cell differences, immunotherapeutic response differences, and drug sensitivity differences between the risk groups. Finally, the genes in the model were experimentally validated. Based on the above analyses, we further selected four IRLs (TFAP2A.AS1, AP000911.1, AL133215.2, and LINC02078) to construct the risk model. The model was associated with oxidative-stress-related genes, especially SOD2 and OGG1. Patients in the high-risk group had a lower overall survival than those in the low-risk group. Riskscore was positively correlated with resting mast cells, neutrophils, and CD8+ T-cells. Patients in the low-risk group showed a greater sensitivity to immunosuppression therapy. In addition, we found that patients with the PIK3CA mutation were more sensitive to chemotherapeutic agents such as dasatinib, afatinib, dinaciclib and pelitinib. The function of AL133215.2 was verified, which was consistent with previous findings, and AL133215.2 exerted a pro-tumorigenic effect. We also found that AL133215.2 was closely associated with oxidative-stress-related pathways. The results suggested that risk modeling might be useful for prognosticating patients with CC and opening up new routes for immunotherapy.
PubMed: 37808187
DOI: 10.3389/fphar.2023.1234181 -
Lung Feb 2024This study investigated the safety and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) re-administration after recovery from...
Efficacy and Safety of Re-administration of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) After EGFR-TKI-Induced Interstitial Lung Disease (CS-Lung-005).
PURPOSE
This study investigated the safety and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) re-administration after recovery from EGFR-TKI-induced interstitial lung disease (ILD).
METHODS
This multicenter retrospective study collected data from consecutive advanced NSCLC patients who underwent EGFR-TKI re-administration after recovery from EGFR-TKI-induced ILD.
RESULTS
Fifty-eight patients were registered. The grades of initial TKI-induced ILD were grade 1 to 4. TKIs used for re-administration were erlotinib for 15 patients, osimertinib for 15, gefitinib for 14, afatinib for 13 patients, and dacomitinib for 1 patient. ILD recurred in 13 patients (22.4%), comprising 3 patients with grade 1, 6 patients with grade 2, and 4 patients with grade 3. No significant associations were found between ILD recurrence and age, smoking history, performance status, time from initial ILD to TKI re-administration, or concomitant corticosteroid use. However, the incidence of ILD recurrence was high in cases of repeated use of gefitinib or erlotinib or first time use of osimertinib at TKI re-administration. The ILD recurrence rate was lowest in patients treated with first time use of gefitinib (8%) or erlotinib (8%), followed by patients treated with repeated use of osimertinib (9%). The response rate, median progression-free survival by TKI re-administration, and median overall survival were 55%, 9.6 and 84.8 months, respectively.
CONCLUSION
This study showed that EGFR-TKI re-administration is a feasible and effective treatment for patients who recovered from EGFR-TKI-induced ILD. Our results indicate that re-administration of EGFR-TKI is an important option for long-term prognosis after recovery from EGFR-TKI-induced ILD.
Topics: Humans; Acrylamides; Aniline Compounds; Antineoplastic Agents; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Indoles; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Pyrimidines; Retrospective Studies; Tyrosine Kinase Inhibitors
PubMed: 38265672
DOI: 10.1007/s00408-023-00669-9 -
Cardio-oncology (London, England) Oct 2023Osimertinib is a third-generation epidermal growth factor receptor (EGFR) inhibitor that is currently the first-line treatment for metastatic EGFR-mutated non-small-cell...
BACKGROUND
Osimertinib is a third-generation epidermal growth factor receptor (EGFR) inhibitor that is currently the first-line treatment for metastatic EGFR-mutated non-small-cell lung cancer (NSCLC) due to its favorable efficacy and tolerability profile compared to previous generations of EGFR inhibitors. However, it can cause uncommon, yet serious, cardiovascular adverse effects.
CASE PRESENTATION
We present the case of a 63-year-old man with EGFR-mutated NSCLC treated with osimertinib who developed new-onset non-ischemic cardiomyopathy with biventricular dysfunction and heart failure in the context of an enlarging pericardial effusion. For the first time, we demonstrate cardiac MR imaging findings associated with osimertinib-associated cardiomyopathy, including focal late gadolinium enhancement and myocardial edema. The patient's biventricular function normalized after initiation of goal-directed medical therapy for heart failure and holding osimertinib. The patient was subsequently started on afatinib, a second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), without recurrence of cardiomyopathy.
CONCLUSIONS
This case highlights the need to better understand osimertinib-induced cardiotoxicity and strategies to optimize oncologic care in patients who develop severe cardiac toxicities from cancer therapy. It further underlines the importance of specialized multidisciplinary care of cancer patients who develop cardiotoxicities to optimize their oncologic outcomes.
PubMed: 37908018
DOI: 10.1186/s40959-023-00190-1 -
ERJ Open Research Mar 2024Afatinib, an irreversible ErbB family inhibitor, is widely used as first-line treatment in advanced lung adenocarcinoma patients harbouring mutant epidermal growth...
BACKGROUND
Afatinib, an irreversible ErbB family inhibitor, is widely used as first-line treatment in advanced lung adenocarcinoma patients harbouring mutant epidermal growth factor receptor (EGFR). With the advancements in next-generation sequencing (NGS), comprehensive research into the clinical impact of co-occurring genetic mutations and the molecular mechanisms of acquired resistance is required for afatinib users.
MATERIALS
From January 2010 to December 2019, we enrolled patients with advanced lung adenocarcinoma with mutations using afatinib as first-line treatment, and we retrospectively collected pre- and post-afatinib treatment specimens from these patients for NGS testing.
RESULTS
Of the 362 enrolled patients, 73 samples (68.9%) from 56 patients successfully returned complete NGS reports. In pre-afatinib treatment specimens, the most frequent co-occurring alterations were , , , , and ; however, they were not related to progression-free survival. Small cell lung cancer transformation, p.T790M, amplification of , , , , cell cycle-regulated genes and , and alterations were identified as acquired resistance mechanisms. p.T790M (p=0.0304) and alterations (p=0.0311) in post-afatinib specimens were significantly associated with longer overall survival, while amplification was significantly associated with poor overall survival (p=0.0324). The co-occurrence of alterations was significantly associated with shorter overall survival (p=0.0298).
CONCLUSIONS
Our results show that the frequent co-occurring alterations in advanced -mutated lung adenocarcinoma did not influence the effectiveness of afatinib. p.T790M is not only the major resistance mechanism to afatinib but also related to favourable survival outcomes. amplification and mutations were associated with poorer overall survival.
PubMed: 38500795
DOI: 10.1183/23120541.00676-2023 -
International Journal of Molecular... Apr 2024Inherited retinal degeneration (RD) constitutes a heterogeneous group of genetic retinal degenerative disorders. The molecular mechanisms underlying RD encompass a...
Inherited retinal degeneration (RD) constitutes a heterogeneous group of genetic retinal degenerative disorders. The molecular mechanisms underlying RD encompass a diverse spectrum of cellular signaling, with the unfolded protein response (UPR) identified as a common signaling pathway chronically activated in degenerating retinas. TRIB3 has been recognized as a key mediator of the PERK UPR arm, influencing various metabolic pathways, such as insulin signaling, lipid metabolism, and glucose homeostasis, by acting as an AKT pseudokinase that prevents the activation of the AKT → mTOR axis. This study aimed to develop a gene-independent approach targeting the UPR TRIB3 mediator previously tested by our group using a genetic approach in mice with RD. The goal was to validate a therapeutic approach targeting TRIB3 interactomes through the pharmacological targeting of EGFR-TRIB3 and delivering cell-penetrating peptides targeting TRIB3 → AKT. The study employed rd10 and P23H RHO mice, with afatinib treatment conducted in p15 rd10 mice through daily intraperitoneal injections. P15 P23H RHO mice received intraocular injections of cell-penetrating peptides twice at a 2-week interval. Our study revealed that both strategies successfully targeted TRIB3 interactomes, leading to an improvement in scotopic A- and B-wave ERG recordings. Additionally, the afatinib-treated mice manifested enhanced photopic ERG amplitudes accompanied by a delay in photoreceptor cell loss. The treated rd10 retinas also showed increased PDE6β and RHO staining, along with an elevation in total PDE activity in the retinas. Consequently, our study demonstrated the feasibility of a gene-independent strategy to target common signaling in degenerating retinas by employing a TRIB3-based therapeutic approach that delays retinal function and photoreceptor cell loss in two RD models.
Topics: Animals; Mice; Retinal Degeneration; Disease Models, Animal; Cell Cycle Proteins; Signal Transduction; Unfolded Protein Response; Protein Serine-Threonine Kinases; Mice, Inbred C57BL; Retina
PubMed: 38731938
DOI: 10.3390/ijms25094716 -
Gene Jul 2023Ferroptosis, being classified as a form of regulated cell death, was driven by the oxidative injury induced by lipid peroxidation (LPO). Recently, ferroptosis has been...
Ferroptosis, being classified as a form of regulated cell death, was driven by the oxidative injury induced by lipid peroxidation (LPO). Recently, ferroptosis has been confirmed to exert a critical effect in the pathogenesis and treatment of various tumors, including gastric cancer (GC). Erastin, as a frequently used ferroptosis inducer, caused ferroptosis by downregulating the xCT expression resulting in increasing reactive oxygen species (ROS) and aggravating the LPO. However, the mechanisms of Erastin in ferroptosis regulation, especially in GC, remain largely elusive. This work firstly demonstrated that Erastin inhibited cell growth and promoted apoptosis and ferroptosis in AGS and BGC823 cells. Then, based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of Erastin-related targets screened by using PharmMapper Web, the P38MAPK signaling was explored and validated in AGS and BGC-823 cells. Besides, the Fer-1 and P38 inhibitor were performed to investigate the mechanisms of ferroptosis induced by Erastin in depth. This work revealed a feedback mode among xCT, ROS and the P38MAPK pathway, which affected each other. It meant that Erastin regulated ferroptosis through the xCT-mediated ROS/P38MAPK signaling feedback loop. In addition, it was noticed that in co-operation with Erastin, the cytotoxic effects of Afatinib on cells were aggravated by further strengthening ferroptosis with activation of the P38MAPK pathway. In summary, those works provided evidence that Erastin plays an important role in increasing the cytotoxic effect on GC cells treated with Afitinib. Furthermore, the Erastin-induced ferroptosis via the xCT-mediated ROS/P38MAPK pathway feedback loop provides new strategies for GC comprehensive treatment.
Topics: Humans; Reactive Oxygen Species; Afatinib; Stomach Neoplasms; Feedback
PubMed: 37169154
DOI: 10.1016/j.gene.2023.147468 -
BMC Cancer Feb 2024This study aimed to evaluate the efficacy and side effects of first-line afatinib treatment in a real-world setting in Vietnam.
BACKGROUND
This study aimed to evaluate the efficacy and side effects of first-line afatinib treatment in a real-world setting in Vietnam.
METHODS
This retrospective study was conducted across nine hospitals in Vietnam. Advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients who received afatinib as first-line therapy between April 2018 and June 2022 were included, and patient medical records were reviewed. Key outcomes were overall response rate (ORR), time-to-treatment failure (TTF), and tolerability.
RESULTS
A total of 343 patients on first-line afatinib were eligible for the study. EGFR exon 19 deletion (Del19) alone was detected in 46.9% of patients, L858R mutation alone in 26.3%, and other uncommon EGFR mutations, including compound mutations, in 26.8%. Patients with brain metastases at baseline were 25.4%. Patients who received 40 mg, 30 mg, and 20 mg as starting doses of afatinib were 58.6%, 39.9%, and 1.5%, respectively. The ORR was 78.1% in the overall population, 82.6% in the Del19 mutation subgroup, 73.3% in the L858R mutation subgroup, and 75.0% in the uncommon mutation subgroup (p > 0.05). The univariate and multivariate analyses indicate that the ORR increased when the starting dose was 40 mg compared to starting doses below 40 mg (83.9% vs. 74.3%, p = 0.034). The median TTF (mTTF) was 16.7 months (CI 95%: 14.8-18.5) in all patients, with a median follow-up time of 26.2 months. The mTTF was longer in patients in the common EGFR mutation subgroup (Del19/L858R) than in those in the uncommon mutation subgroup (17.5 vs. 13.8 months, p = 0.045) and in those without versus with brain metastases at baseline (17.5 vs. 15.1 months, p = 0.049). There were no significant differences in the mTTF between subgroups based on the starting dose of 40 mg and < 40 mg (16.7 vs. 16.9 months, p > 0.05). The most common treatment-related adverse events (any grade/grade ≥ 3) were diarrhea (55.4%/3.5%), rash (51.9%/3.2%), paronychia (35.3%/5.0%), and stomatitis (22.2%/1.2%).
CONCLUSIONS
Afatinib demonstrated clinical effectiveness and good tolerability in Vietnamese EGFR-mutant NSCLC patients. In our real-world setting, administering a starting dose below 40 mg might result in a reduction in ORR; however, it might not have a significant impact on TTF.
Topics: Humans; Afatinib; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Cohort Studies; ErbB Receptors; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Retrospective Studies; Vietnam
PubMed: 38317094
DOI: 10.1186/s12885-024-11891-w -
Pharmaceuticals (Basel, Switzerland) Jul 2023A series of novel enantiopure isoxazolidine derivatives were synthesized and evaluated for their anticancer activities against three human cancer cell lines such as...
In Vitro and In Silico Evaluation of Antiproliferative Activity of New Isoxazolidine Derivatives Targeting EGFR: Design, Synthesis, Cell Cycle Analysis, and Apoptotic Inducers.
A series of novel enantiopure isoxazolidine derivatives were synthesized and evaluated for their anticancer activities against three human cancer cell lines such as human breast carcinoma (MCF-7), human lung adenocarcinoma (A-549), and human ovarian carcinoma (SKOV3) by employing MTT assay. The synthesized compounds were characterized by NMR and elemental analysis. Results revealed that all the synthesized compounds displayed significant inhibition towards the tested cell lines. Among them, and , which differ only by the presence of an ester group at the C-3 position and small EDG (methyl) at the C-5 position of the phenyl ring (), were the most active derivatives in attenuating the growth of the three cells in a dose-dependent manner. The IC for were 17.7 ± 1 µM (MCF-7), 12.1 ± 1.1 µM (A-549), and 13.9 ± 0.7 µM (SKOV3), and for were 9.7 ± 1.3µM (MCF-7), 9.7 ± 0.7µM (A-549), and 6.5 ± 0.9µM (SKOV3), respectively, which were comparable to the standard drug, doxorubicin. The enzymatic inhibition of and against EGFR afforded good inhibitory activity with IC of 0.298 ± 0.007 μM and 0.484 ± 0.01 µM, respectively, close to the positive control, Afatinib. Compound arrested the cell cycle in the S phase in MCF-7 and SKOV3 cells, and in the G2/M phase in the A549 cell; however, induced G0/G1 phase cell cycle arrest, and inhibited the progression of the three cancer cells, together with significant apoptotic effects. The docking study of compounds and into EGFR ATP-active site revealed that it fits nicely with good binding affinity. The pharmacokinetic and drug-likeness scores revealed notable lead-like properties. At 100 ns, the dynamic simulation investigation revealed high conformational stability in the EGFR binding cavity.
PubMed: 37513936
DOI: 10.3390/ph16071025