scholarly journals Genomic characterization and outcome evaluation of kinome fusions in lung cancer revealed novel druggable fusions

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Binghao Li ◽  
Hao Qu ◽  
Jing Zhang ◽  
Weibo Pan ◽  
Meng Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Low Frequency ◽  
Stage Iv ◽  
Outcome Evaluation ◽  
Driver Mutations ◽  
Gene Fusions ◽  
Comprehensive Overview ◽  
Unique Gene

AbstractKinase fusions represent an important type of somatic alterations that promote oncogenesis and serve as diagnostic markers in lung cancer. We aimed to identify the landscape of clinically relevant kinase fusions in Chinese lung cancer and to explore rare kinase rearrangements; thus, providing valuable evidence for therapeutic decision making. We performed genomic profiling of 425 cancer-relevant genes from tumor/plasma biopsies from a total of 17,442 Chinese lung cancer patients using next generation sequencing (NGS). Patients’ clinical characteristics and treatment histories were retrospectively studied. A total of 1162 patients (6.66%; 1162/17,442) were identified as having kinase fusions, including 906 adenocarcinomas (ADCs) and 35 squamous cell carcinomas (SCCs). In ADC, 170 unique gene fusion pairs were observed, including rare kinase fusions, SLC12A2-ROS1, NCOA4-RET, and ANK3-RET. As for SCC, 15 unique gene fusions were identified, among which the most frequent were EML4-ALK and FGFR3-TACC3. Analyses of oncogenic mutations revealed a dual role for the gene fusions, CCDC6-RET and FGFR3-TACC3, in driving oncogenesis or serving as acquired resistance mechanisms to kinase inhibitors. In addition, our real-world evidence showed that patients with recurrent kinase fusions with low frequency (two occurrences) could benefit from treatment with kinase inhibitors’ off-label use. Notably, patients with stage IV ADC who had novel RORB-ALK or AFF2-RET fusions, but no other known oncogenic driver mutations, demonstrated favorable clinical outcomes on tyrosine kinase inhibitors. Our data provide a comprehensive overview of the landscape of oncogenic kinase fusions in lung cancer, which assist in recognizing potentially druggable fusions that can be translated into therapeutic applications.

Advances in the Treatment of Non-Small Cell Lung Cancer

2014 ◽  
Vol 12 (5S) ◽  
pp. 764-767 ◽  
Author(s):  
Leora Horn
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Small Cell ◽  
Driver Mutations ◽  
Annual Conference ◽  
Small Cell Lung ◽  
Nccn Guidelines

Clinical trial data continue to emerge on treatments in advanced non-small cell lung cancer (NSCLC), supporting the strategy that histology and molecular driver mutations should guide treatment selection. During her presentation at the NCCN 19th Annual Conference, Dr. Leora Horn highlighted 3 specific areas in which the 2014 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for NSCLC focus attention: updates on the assortment of chemotherapy options, targeted therapies and how acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors appears to have become the catalyst of the development of newer-generations of agents, and the revisited role of newer immunotherapeutic options.

scholarly journals Real-world osimertinib for EGFR mutation-positive non-small-cell lung cancer with acquired T790M mutation

2020 ◽  
Vol 16 (21) ◽  
pp. 1537-1547
Author(s):  
Fumio Imamura ◽  
Madoka Kimura ◽  
Yukihiro Yano ◽  
Masahide Mori ◽  
Hidekazu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Clinical Trial Registration

Aim: Osimertinib is a key drug for EGFR mutation-positive non-small-cell lung cancer (NSCLC). As the hazards ratio of overall survival in comparison with first-generation EGFR-tyrosine kinase inhibitors was almost similar between FLAURA and ARCHER 1050, salvage use of osimertinib is still a treatment option. Patients & methods: We retrospectively analyzed the clinical courses of EGFR mutation-positive NSCLC patients who were potential candidates for salvage osimertinib. Results: Among 524 patients enrolled from five hospitals, 302 patients underwent biopsy, with 52.6% detection rate of T790M. Osimertinib was administered in 93.6% of the T790M-positive patients. The overall response rate and median progression-free survival time of osimertinib were calculated with 147 patients, to be 55.6% and 17.2 months, respectively. Conclusion: Osimertinib is active for T790M-driven acquired resistance in EGFR-mutant NSCLC, but the detection of T790M was unsatisfactory. Clinical Trial Registration: UMIN000028989 (UMIN Clinical Trials Registry)

scholarly journals Tumor immune microenvironment in non-small cell lung cancer with EGFR mutation before and after EGFR-TKIs treatment

2021 ◽  
Author(s):  
chao wang ◽  
lihui liu ◽  
sini li ◽  
hua bai ◽  
jie wang
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Treatment Time ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Before And After ◽  
Almost All ◽  
Egfr Tkis

Lung cancer is the most common cancer and a leading cause of death from cancer in men and women in the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are considered as the first-line treatment of EGFR mutated NSCLC. However, almost all patients eventually develop acquired resistance to EGFR-TKIs, with a median PFS of 9-14 months. With the development of immunotherapy, people realize that the interaction between tumor immune microenvironment (TIME) and tumor cells can also affect EGFR-TKIs treatment. TIME contains a variety of elements and previous researches of TIME in EGFR-TKIs therapy on NSCLC are decentralized. Here, we review the characteristics of TIME in NSCLC from EGFR-TKIs therapy and its role in TKIs resistance.

Lung Cancer in 2013: State of the Art Therapy for Metastatic Disease

2013 ◽  
pp. 339-346
Author(s):  
Frances A. Shepherd ◽  
Paul A. Bunn ◽  
Luis Paz-Ares
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Poor Performance ◽  
Initial Therapy ◽  
Egfr Mutations ◽  
Molecular Testing ◽  
Molecular Features ◽  
Platinum Doublet

Lung cancer is the leading worldwide cause of cancer death and the majority of patients present with metastatic stage IV disease. At diagnosis, clinical, histologic, and molecular features must be considered in therapeutic decision-making for systemic therapy. Molecular testing for at least epidermal growth factor receptor ( EGFR) and ALK should be performed in all patients before therapy. Platinum doublet chemotherapy may be considered for “fit” patients who do not have a molecular driver genetic abnormality. Bevacizumab can be considered for addition to the doublet in patients with nonsquamous cancers who have no contraindications. A pemetrexed combination is considered only in nonsquamous histology. Patients with EGFR mutations or ALK fusions should be treated with erlotinib or crizotinib, respectively, even in patients with tumor-related poor performance. The tyrosine-kinase inhibitors (TKIs) may be continued until multisite, symptomatic progression. For patients initially treated with a platinum doublet, maintenance chemotherapy with pemetrexed, erlotinib, gemcitabine, or possibly docetaxel is an option with selection based on clinical features, histology, type of initial therapy, and response to first-line therapy.

scholarly journals Molecular findings reveal possible resistance mechanisms in a patient with ALK-rearranged lung cancer: a case report and literature review

ESMO Open ◽  
2019 ◽  
Vol 4 (5) ◽  
pp. e000561 ◽  
Author(s):  
Anastasia Kougioumtzi ◽  
Panagiotis Ntellas ◽  
Eirini Papadopoulou ◽  
George Nasioulas ◽  
Eleftherios Kampletsas ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Disease Progression ◽  
Kinase Inhibitors ◽  
Wide Spectrum ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Molecular Testing ◽  
Liquid Biopsies ◽  
Disease Biology ◽  
Remarkable Progress

Background: Non-small-cell lung cancer (NSCLC) is recognised as a particularly heterogeneous disease, encompassing a wide spectrum of distinct molecular subtypes. With increased understanding of disease biology and mechanisms of progression, treatment of NSCLC has made remarkable progress in the past two decades. Molecular testing is considered the hallmark for the diagnosis and treatment of NSCLC, with liquid biopsies being more and more often applied in the clinical setting during the recent years. Rearrangement of the ALK gene which results in the generation of fusion oncogenes is a common molecular event in NSCLCs. Among ALK fusion transcripts, EML4-ALK fusion is frequently observed and can be targeted with ALK tyrosine kinase inhibitors (TKI). However, acquired resistance and disease progression in many cases are inevitable.Method: Here, we present the case of a patient with NSCLC treated with TKIs, in which molecular profiling of the tumour was performed with different methods of tissue and plasma testing at each disease progression. A review of the literature was further conducted to offer insights into the resistance mechanisms of ALK-rearranged NSCLC.Conclusions: Based on the results, the EML4-ALK fusion initially detected in tumour tissue was preserved throughout the course of the disease. Two additional ALK mutations were later detected in the tissue and plasma and are likely to have caused resistance to the administered TKIs. Continued research into the mechanisms of acquired resistance is required in order to increase the benefit of the patients treated with targeted ALK TKIs.

scholarly journals Combating Acquired Resistance to Tyrosine Kinase Inhibitors in Lung Cancer

2015 ◽  
pp. e165-e173 ◽  
Author(s):  
Christine M. Lovly
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Initial Response ◽  
In Vitro Models ◽  
Tumor Biopsy

The prospective identification and therapeutic targeting of oncogenic tyrosine kinases with tyrosine kinase inhibitors (TKIs) has revolutionized the treatment for patients with non–small cell lung cancer (NSCLC). TKI therapy frequently induces dramatic clinical responses in molecularly defined cohorts of patients with lung cancer, paving the way for the implementation of precision medicine. Unfortunately, acquired resistance, defined as tumor progression after initial response, seems to be an inevitable consequence of this treatment approach. This brief review will provide an overview of the complex and heterogeneous problem of acquired resistance to TKI therapy in NSCLC, with a focus on EGFR-mutant and ALK-rearranged NSCLC. In vitro models of TKI resistance and analysis of tumor biopsy samples at the time of disease progression have generated breakthroughs in our understanding of the spectrum of mechanisms by which a tumor can thwart TKI therapy and have provided an important rationale for the development of novel approaches to delay or overcome resistance. Numerous ongoing clinical trials implement strategies, including novel, more potent TKIs and rational combinations of targeted therapies, some of which have already proven effective in surmounting therapeutic resistance.

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