Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions

Biomedicines, Journal Year: 2024, Volume and Issue: 12(2), P. 297 - 297

Published: Jan. 27, 2024

This review comprehensively explores the intricate landscape of anaplastic lymphoma kinase (ALK), focusing specifically on its pivotal role in non-small cell lung cancer (NSCLC). Tracing ALK's discovery, from fusion with nucleolar phosphoprotein (NPM)-1 large non-Hodgkin's (ALCL) 1994, elucidates subsequent impact ALK gene alterations various malignancies, including inflammatory myofibroblastoma and NSCLC. Approximately 3-5% NSCLC patients exhibit complex rearrangements, leading to approval six ALK-tyrosine inhibitors (TKIs) by 2022, revolutionizing treatment for advanced metastatic + Notably, second-generation TKIs such as alectinib, ceritinib, brigatinib have emerged address resistance issues initially associated pioneer ALK-TKI, crizotinib.

Language: Английский

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Rare dual MYH9–ROS1 fusion variants in a patient with lung adenocarcinoma: A case report

Medicine, Journal Year: 2025, Volume and Issue: 104(4), P. e41350 - e41350

Published: Jan. 24, 2025

Rationale: ROS proto-oncogene 1 (ROS1) fusion is a rare but important driver mutation in non-small cell lung cancer, which usually shows significant sensitivity to small molecule tyrosine kinase inhibitors. With the widespread application of next-generation sequencing (NGS), more fusions and co-mutations ROS1 have been discovered. Non-muscle myosin heavy chain 9 (MYH9) partner gene as reported. Here, we report an even case with coexistence short long variants MYH9–ROS1 at RNA level accompanied by TP53 mutation, insensitively antitumor therapy. Patient concerns diagnosis: A 37-year-old nonsmoking man was diagnosed stage IVB (T4N3M1c) adenocarcinoma. The tumor identified MYH9 (exon 37)–ROS1 35) rearrangement DNA DNA-NGS analysis lymph node biopsy tissue March 2023. Interestingly, it transcribed into (M36, R36) R35) RNA-NGS analysis. Interventions: First-line inhibitors crizotinib given firstly, showing partial response (PR) progression within 3 months. To determine resistance mechanism genetic variation, were performed again on new August Outcomes: Rare again, typical mechanisms not observed. Switching lorlatinib resulted brief PR about 2 Subsequent courses system chemotherapy provided short-term less than patient died total survival 10 Lessons: We must pay attention dual fusions, may affect efficacy ROS1-tyrosine targeted

Language: Английский

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New Generations of Tyrosine Kinase Inhibitors in Treating NSCLC with Oncogene Addiction: Strengths and Limitations

Cancers, Journal Year: 2023, Volume and Issue: 15(20), P. 5079 - 5079

Published: Oct. 20, 2023

Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring most driver gene alterations. Starting from first generation, research rapidly moved to development newer, more selective generations TKIs, obtaining improved results in terms disease control and survival. However, use novel TKIs is not without limitations. We reviewed main obtained, as well ongoing clinical trials oncogene-addicted NSCLC, together biology underlying their potential strengths Across alterations, allowed delayed resistance, prolonged survival, brain penetration compared previous generations, although different toxicity profiles, that generally further lines front-line treatment. anticipated positioning generation leads abolishing possibility TKI sequencing any role generations. In addition, under pressure such potent drugs, resistant clones emerge complex hard-to-target resistance mechanisms. Deeper knowledge tumor drug properties will help identify new strategies, including combinatorial treatments, continue improving NSCLC.

Language: Английский

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Associations between immune cell phenotypes and lung cancer subtypes: insights from mendelian randomization analysis

BMC Pulmonary Medicine, Journal Year: 2024, Volume and Issue: 24(1)

Published: May 16, 2024

Abstract Introduction Lung cancer is a common malignant tumor, and different types of immune cells may have effects on the occurrence development lung subtypes, including squamous cell carcinoma (LUSC) adenocarcinoma (LUAD). However, causal relationship between phenotype still unclear. Methods This study utilized comprehensive dataset containing 731 phenotypes from European Bioinformatics Institute (EBI) to evaluate potential LUSC LUAD using inverse variance weighted (IVW) method in Mendelian randomization (MR). Sensitivity analyses, MR-Egger intercept, Cochran Q test, others, were conducted for robustness results. The results further validated through meta-analysis data Transdisciplinary Research Into Cancer (TRICL) data. Additionally, confounding factors excluded ensure findings. Results Among final selection 729 phenotypes, three exhibited statistically significant with LUSC. CD28 expression resting CD4 regulatory T (OR 1.0980, 95% CI: 1.0627–1.1344, p < 0.0001) CD45RA + CD28- CD8 %T 1.0011, 1.0007; 1.0015, associated increased susceptibility Conversely, CCR2 monocytes 0.9399, 0.9177–0.9625, was correlated decreased risk no relationships established any LUAD. Conclusion demonstrates that specific are but not While these findings derived solely populations, they provide clues deeper understanding immunological mechanisms underlying offer new directions future therapeutic strategies preventive measures.

Language: Английский

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Exploring the Profiles of ROS1 Tyrosine Kinase: A Structural Analysis of G2032R and D2033N Mutations

International Journal of Applied and Basic Medical Research, Journal Year: 2025, Volume and Issue: 15(1), P. 4 - 10

Published: Jan. 1, 2025

Background: ROS1, a proto-oncogene, drives cancer through chromosomal fusions. The G2032R and D2033N mutations, common in ROS1-rearranged non-small cell lung cancer, hinder crizotinib treatment. We investigate these mutations’ impact on ROS1 structure molecular dynamics (MD) simulations, revealing destabilization. Our findings shed light how mutations contribute to development. Materials Methods: crystal of human (PDB ID: 7z5x) served as the template for homology modeling further mutation insertion substitutions introduced using Swiss-PdbViewer. MD simulations were conducted wild-type (WT) mutant kinase domains explore structural changes interactions. Results: initial model was constructed, incorporating missing loop residues then utilized simulation studies. examination conformational WT, G2032R, proteins involved observing alterations C-alpha protein. observed that resulted deviations trajectory over 500 ns period. Consequently, unveiled significant induced by affecting protein stability dynamics, particularly regions such ATP binding active sites. Conclusion: study constructed an used it studies examine mutants. Notably, our observations revealed caused trajectory. significantly alter structure, its offering key insights into their role disease

Language: Английский

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Effects of Tp53 Gene Mutations on the Survival of Non-Small Cell Lung Cancer (NSCLC); A Short Review

Cancer Management and Research, Journal Year: 2025, Volume and Issue: Volume 17, P. 65 - 82

Published: Jan. 1, 2025

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide.Mutations within TP53 gene represent critical molecular events in NSCLC, contributing to tumorigenesis pulmonary epithelial tissues.TP53 a widely researched prognostic indicator and pathological investigations have revealed weak mild negative predictive effect for TP53.Mutated p53 protein may some pro-oncogenic impact, variations change tumor inhibitors into oncogenes.The diverse mutational spectrum NSCLC with different mutations linked varied treatment responses.In contrast, first-line chemotherapeutics this progress are limited, however, randomized trials new shown significant survival benefits.This review highlighted influence on pathological-sensitivity overall outcomes NSCLC.Further research needed explore mutation-specific pathways their effects progression effectiveness.

Language: Английский

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Impact and reproducibility of in-house targeted next-generation sequencing biomarker testing in non-small cell lung cancer: an Italian multi-institutional experience

Journal of Molecular Diagnostics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Next-generation sequencing (NGS) allows the detection of multiple genetic targets in different tumor types. This study aimed to confirm benefits implementing NGS testing in-house for non-small cell lung cancer (NSCLC) samples molecular pathology laboratories. A multi-institutional was conducted evaluate analytical performance, turnaround time, and feasibility 50 genes from 283 NSCLC samples. The first phase a retrospective with inter-laboratory (21 samples) second prospective intra-laboratory (262 samples). showed 100% success rate DNA RNA, high concordance (95.2%), strong correlation (R2 = 0.94) between observed expected SNV/indel allele fraction. 99.2% 98% RNA. identified 285 relevant variants (81.1% SNV/indel, 9.8% CNV, 9.1% gene fusions). Co-mutations potential clinical relevance were detected 20.5% positive main oncogenic drivers NSCLC. In addition, 11% wild type alterations other genes. experience median time sample processing report 4 days. conclusion, this demonstrates advantages

Language: Английский

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Unravelling the role of key genes in oral cancer progression: A comprehensive review

Oral Oncology Reports, Journal Year: 2024, Volume and Issue: 10, P. 100384 - 100384

Published: April 12, 2024

• In worldwide, 90% of oral cancer are caused by squamous cell carcinoma (OSCC), also common seen in the Indian subcontinent. Genetic mutations key genes such as EGFR, HER2 and TP53 important development cancer. Critical screening identification molecular biomarkers essential to developing new treatment diagnostic approaches. Oncogenes tumor suppressor play a significant role spread indicating significance targeted genetic therapy.

Language: Английский

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The Advantage of Targeted Next-Generation Sequencing over qPCR in Testing for Druggable EGFR Variants in Non-Small-Cell Lung Cancer

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(14), P. 7908 - 7908

Published: July 19, 2024

The emergence of targeted therapies in non-small-cell lung cancer (NSCLC), including inhibitors epidermal growth factor receptor (EGFR) tyrosine kinase, has increased the need for robust companion diagnostic tests. Nowadays, detection actionable variants exons 18-21 EGFR gene by qPCR and direct DNA sequencing is often replaced next-generation (NGS). In this study, we evaluated usefulness NGS druggable testing clinical NSCLC material previously analyzed IVD-certified test with respect to reference material. We tested 59 tissue cytology specimens using 'TruSight Tumor 15' assay (Illumina) 'cobas mutation v2' (Roche Diagnostics). sensitivity specificity were biosynthetic biological known allelic frequencies (VAF) variants. demonstrated a sufficient lower limit applications (VAF < 5%) material; all correctly identified. showed high repeatability VAF assessment between runs (CV% from 0.02 3.98). material, overall concordance was 76.14% (Cohen's Kappa = 0.5933). majority discordant results concerned false-positive exon 20 insertions qPCR. A total 9 out (15%) samples one or more both assays. Additionally, observed TP53 be frequently co-mutated EGFR-positive patients. conclusion, number superior features over variant (exact identification variants, calculation frequency, analytical sensitivity), which might enhance basic report.

Language: Английский

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Lung cancer biomarkers: Raising the clinical value of the classical and the new ones

Tumor Biology, Journal Year: 2024, Volume and Issue: 46(s1), P. S1 - S7

Published: March 19, 2024

Blood-based diagnostics for lung cancer support the diagnosis, estimation of prognosis, prediction, and monitoring therapy response in patients. The clinical utility serum tumor markers has considerably increased due to developments protein analytics biomarker studies, exploration preanalytical influencing conditions, interpretation combinations individual kinetics, as well implementation biostatistical models. In addition, circulating DNA (ctDNA) other liquid biopsy are playing an increasingly prominent role molecular characterization evolution over time. Thus, modern biomarkers may contribute individualized companion provide a sensitive guidance patients throughout course their disease. this special edition on Tumor Markers Lung Cancer, experts summarize recent laboratory give outlook future challenges opportunities.

Language: Английский

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