Rare molecular subtypes of lung cancer

Nature Reviews Clinical Oncology, Год журнала: 2023, Номер 20(4), С. 229 - 249

Опубликована: Фев. 20, 2023

Язык: Английский

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IL6 Mediates Suppression of T- and NK-cell Function in EMT-associated TKI-resistant EGFR-mutant NSCLC

Clinical Cancer Research, Год журнала: 2023, Номер 29(7), С. 1292 - 1304

Опубликована: Янв. 3, 2023

Patients with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are initially responsive to tyrosine kinase inhibitors (TKI). However, therapeutic resistance eventually emerges, often via secondary or EGFR-independent mechanisms such as epithelial-to-mesenchymal transition. Treatment options after EGFR-TKI limited anti-PD-1/PD-L1 typically display minimal benefit. Given that IL6 is associated worse outcomes in patients NSCLC, we investigate whether part contributes this immunosuppressed phenotype.We utilized a syngeneic genetically engineered mouse model (GEMM) of EGFR-mutant NSCLC the effects on tumor microenvironment and combined efficacy inhibition anti-PD-1 therapy. Corresponding vitro studies used human lines clinical specimens.We identified tumors which have oncogene-independent acquired EGFR-TKIs were more mesenchymal had markedly enhanced secretion. In GEMMs, depletion activation infiltrating natural killer (NK)- T-cell subpopulations decreased immunosuppressive regulatory T Th17 populations. Inhibition increased NK- cell-mediated killing osimertinib-resistant cells culture. blockade sensitized GEMM PD-1 through an increase tumor-infiltrating IFNγ+ CD8+ cells.These data indicate upregulated suppressed T- NK-cell function. antitumor immunity therapy warranting future combinatorial investigations.

Язык: Английский

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3D bioprinted vascularized lung cancer organoid models with underlying disease capable of more precise drug evaluation

Biofabrication, Год журнала: 2023, Номер 15(3), С. 034104 - 034104

Опубликована: Май 26, 2023

Abstract Despite encouraging progress in the development of vitro cancer models, models that simultaneously recapitulate complexity tumor microenvironment and its diverse cellular components genetic properties remain lacking. Here, an advanced vascularized lung (LC) model is proposed, which includes patient-derived LC organoids (LCOs), fibroblasts, perfusable vessels using 3D bioprinting technology. To better biochemical composition native tissues, a porcine lung-derived decellularized extracellular matrix (LudECM) hydrogel was produced to offer physical cues cells microenvironment. In particular, idiopathic pulmonary fibrosis-derived fibroblasts were used implement fibrotic niches similar actual human fibrosis. It shown they increased cell proliferation expression drug resistance-related genes LCOs with addition, changes resistance sensitizing targeted anti-cancer drugs fibrosis significantly greater LudECM than Matrigel. Therefore, assessment responsiveness can help determine appropriate therapy for patients accompanied by Furthermore, it expected this approach could be utilized therapies or identification biomarkers

Язык: Английский

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Developments in predictive biomarker testing and targeted therapy in advanced stage non-small cell lung cancer and their application across European countries

The Lancet Regional Health - Europe, Год журнала: 2024, Номер 38, С. 100838 - 100838

Опубликована: Март 1, 2024

In the past two decades, treatment of metastatic non-small cell lung cancer (NSCLC), has undergone significant changes due to introduction targeted therapies and immunotherapy. These advancements have led need for predictive molecular tests identify patients eligible therapy. This review provides an overview development current application biomarker testing in European with advanced stage NSCLC. Using data from eleven countries, we conclude that recommendations are incorporated national guidelines across Europe, although there differences their comprehensiveness. Moreover, availability recently EMA-approved varies between countries. Unfortunately, routine assessment national/regional rates is limited. As a result, it remains uncertain which proportion NSCLC Europe receive adequate testing. Lastly, Molecular Tumor Boards (MTBs) discussion test results widely implemented, but composition functioning lacking. The establishment MTB can provide framework interpreting rare or complex mutations, facilitating appropriate decision-making, ensuring quality control.

Язык: Английский

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Patient‐derived xenograft model in cancer: establishment and applications

MedComm, Год журнала: 2025, Номер 6(2)

Опубликована: Янв. 19, 2025

Abstract The patient‐derived xenograft (PDX) model is a crucial in vivo extensively employed cancer research that has been shown to maintain the genomic characteristics and pathological structure of patients across various subtypes, metastatic, diverse treatment histories. Various strategies utilized PDX models can offer valuable insights into mechanisms tumor progression, drug resistance, development novel therapies. This review provides comprehensive overview establishment applications models. We present an history current status models, elucidate construction methodologies for different tumors, conduct comparative analysis highlight distinct advantages limitations this relation other are elucidated domain comprehending underlying therapy, which highlights broad fields chemotherapy, targeted delivery systems, combination antibody–drug conjugates radiotherapy. Furthermore, with multiomics single‐cell analyses also emphasized. application clinical personalized medicine additionally

Язык: Английский

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Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With Non–Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertions

Journal of Clinical Oncology, Год журнала: 2023, Номер 41(26), С. 4218 - 4225

Опубликована: Июнь 29, 2023

PURPOSE Although several agents targeting epidermal growth factor receptor ( EGFR ) exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to inhibition of wild-type (WT) are common with these affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral tyrosine kinase inhibitor (TKI) a novel pyrrolopyrimidine scaffold leading enhanced selectivity for ex20ins-mutant versus WT potent cell in ex20ins-positive lines. METHODS This phase 1/2a study zipalertinib enrolled patients recurrent or metastatic non–small-cell lung cancer (NSCLC) previously treated platinum-based chemotherapy. RESULTS Seventy-three were at dose levels including 30, 45, 65, 100, 150 mg orally twice day. Patients predominantly female (56%), had median age 64 years, heavily pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent received non-ex20ins TKIs 3/73 (4.1%) ex20ins TKIs. The most frequently reported treatment-related adverse events any grade included rash (80%), paronychia (32%), diarrhea (30%), fatigue (21%). No cases 3 higher drug-related observed 100 day below. Objective responses occurred across all tested, confirmed partial response (PR) 28/73 (38.4%) response-evaluable patients. Confirmed PRs seen 16/39 (41%) CONCLUSION has encouraging preliminary antitumor activity NSCLC, acceptable safety profile, low frequency high-grade rash.

Язык: Английский

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Novel therapeutic strategies for rare mutations in non-small cell lung cancer

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Май 5, 2024

Lung cancer is still the leading cause of cancer-related mortality. Over past two decades, management non-small cell lung (NSCLC) has undergone a significant revolution. Since first identification activating mutations in epidermal growth factor receptor (EGFR) gene 2004, several genetic aberrations, such as anaplastic lymphoma kinase rearrangements (ALK), neurotrophic tropomyosin (NTRK) and hepatocyte (MET), have been found. With development sequencing technology, targeted drugs for rare mutations, multikinase inhibitors, provided new strategies treating patients with mutations. Patients who harbor this type oncologic driver might acquire greater survival benefit from use therapy than chemotherapy immunotherapy. To date, more agents regimens can achieve satisfactory results NSCLC. In review, we focus on recent advances highlight approval molecular NSCLC drivers.

Язык: Английский

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The changing treatment landscape of EGFR-mutant non-small-cell lung cancer

Nature Reviews Clinical Oncology, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 29, 2024

Язык: Английский

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EGFR exon 20 insertion mutations and ERBB2 mutations in lung cancer: a narrative review on approved targeted therapies from oral kinase inhibitors to antibody-drug conjugates

Translational Lung Cancer Research, Год журнала: 2023, Номер 12(7), С. 1590 - 1610

Опубликована: Июль 1, 2023

This review will provide an overview of

Язык: Английский

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Overview on Therapeutic Options in Uncommon EGFR Mutant Non-Small Cell Lung Cancer (NSCLC): New Lights for an Unmet Medical Need

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(10), С. 8878 - 8878

Опубликована: Май 17, 2023

The majority of epidermal growth factor receptor (EGFR) mutations (85-90%) are exon 19 deletions and L858R point 21, characterized by high sensitivity to EGFR-tyrosine kinase inhibitors (TKIs). Less is known about uncommon (10-15% EGFR mutations). predominant mutation types in this category include 18 mutations, 21 L861X, 20 insertions, S768I. This group shows a heterogeneous prevalence, partly due different testing methods the presence compound which some cases can lead shorter overall survival TKIs compared simple mutations. Additionally, EGFR-TKI may also vary depending on specific tertiary structure protein. best strategy remains uncertain, data EGFR-TKIs efficacy based few prospective retrospective series. Newer investigational agents still under study, there no other approved treatments targeting Defining treatment option for patient population an unmet medical need. objective review evaluate existing outcomes, epidemiology, clinical characteristics lung cancer patients with rare focus intracranial activity response immunotherapy.

Язык: Английский

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