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The presence of anaplastic lymphoma kinase (ALK) rearrangement defines a molecular subtype of non-small-cell lung cancer (NSCLC). ALK inhibitors confer significant clinical benefits in patients with ALK-positive advanced NSCLC; therefore, it is of great clinical significance to select accurate, rapid, and appropriate ALK testing methods to screen f...
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... resistance mechanisms include (i) secondary mutations in ALK kinase domain 56-59 ; (ii) ALK copy number gain 60-62 ; and (iii) bypass activation of alternative oncogenic pathways, such as EGFR, KRAS, IGF-1R, and KIT 63-65 . The first generation of small molecular ALKI, crizotinib and the second generation of ceritinib, alectinib, brigatinib, and ensartinib target both treatment naïve and crizotinib-resistant patients with acquired mutations; furthermore, the third ALKI lorlatinib showed efficacy to overcome the resistance of previous ALKIs ( Table 2 ) [66][67][68] . In addition, the possibility of rechallenging therapies may occur when lorlatinib-resistant patients developed an ALK L1198F mutation, and the patient was subsequently re-treated with crizotinib obtaining again disease remission 69 , 70 . ...Similar publications
MERTK and AXL are members of the TAM family of receptor tyrosine kinases and are abnormally expressed in 69% and 93% of non-small cell lung cancers (NSCLCs), respectively. Expression of MERTK and/or AXL provides a survival advantage for NSCLC cells and correlates with lymph node metastasis, drug resistance, and disease progression in patients with...
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... These "non-functional" rearrangements might indicate ALK fusions by fluorescence in situ hybridization (FISH) (10). There are also some guidelines and expert consensus that DNA-seq NGS may identify atypical or intergenic fusions (11). Another case of an antisense rearrangement of ALK was previously reported, in which a complex tripartite rearrangement involving multiple DNA fusion junctions was formed between YY1P2 downstream, EML4, and ALK. ...
Next-generation sequencing technology has enabled the identification of fusion partners of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer, and various ALK fusion partners have been confirmed. Here, a novel rhabdomyosarcoma 2-associated transcript (RMST)-ALK rearrangement was identified in an 80-year-old Chinese man with advanced lung adenocarcinoma. The patient was prescribed ceritinib and achieved a partial response, which has been sustained for more than 18 months. This is the first report of the RMST-ALK rearrangement, and we showed that a patient with lung adenocarcinoma carrying this rearrangement can benefit from ceritinib treatment; therefore, this is a significant finding in clinical practice.
... A recent clinical study demonstrated promising results with high response and complete resection rates with ALK TKI as neoadjuvant therapy in 11 patients with stage I-IIIa ALK-rearranged NSCLC [44]. Our study supports the clinical use of DNA-NGS for detecting ALK rearrangements in lung cancer as recommended by the Chinese RATICAL study [45]. ...
Next-generation sequencing (NGS) is rapidly becoming routine in clinical oncology practice to identify therapeutic biomarkers, including gene rearrangements in anaplastic lymphoma kinase (ALK). Our study investigated the concordance of ALK positivity evaluated by DNA-based NGS with orthogonal ALK testing methods such as fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and RNA-based NGS (RNA-NGS). Thirty-eight patients with lung adenocarcinoma who were detected with ALK rearrangements using DNA-NGS and also had adequate tissue samples submitted for FISH, IHC, and RNA-NGS, were included in this study. Of the 38 patients, RNA samples from 3 patients failed quality control for RNA-NGS. The concordance of ALK positivity was calculated relative to DNA-NGS results. The concordance rates were 97.1% (34/35) for RNA-NGS, 94.7% (36/38) for IHC, and 97.4% (37/38) for FISH. DNA-NGS detected single ALK rearrangements in 14 (35.0%) patients and complex ALK rearrangements in 26 (65.0%). RNA-NGS detected only single transcripts of the primary ALK fusions. A novel LANCL1-ALK (L7:A20) detected using DNA-NGS was detected as EML4-ALK (E13:A20) transcripts using RNA-NGS. Interestingly, patients with single ALK rearrangements were more likely to be detected with atypical isolated red signals (p < 0.001), while patients with complex ALK rearrangements were more likely to be detected with atypical split red and green signals less than 2 signal diameters apart (p < 0.001). Our study highlights the reliability of NGS in the accurate detection of specific ALK fusion variants and concomitant mutations that are crucial for individualized treatment decisions in patients with lung cancer.
Iruplinalkib (Trade name: 启欣可®; Code name: WX-0593), a highly selective oral anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI), is being developed by Qilu Pharmaceutical Co., Ltd. for the treatment of ALK-positive (ALK+) or ROS1-positive (ROS1+) non-small cell lung cancer (NSCLC). In June 2023, iruplinalkib was approved in China for the treatment of patients with locally advanced or metastatic ALK+ NSCLC who have progressed after prior crizotinib therapy or are intolerant to crizotinib. This article summarizes the milestones in the development of iruplinalkib leading to this first approval for the treatment of patients with locally advanced or metastatic ALK+ NSCLC.
To provide its therapeutic effects, High-Intensity Focused Ultrasound (HIFU) treatment makes use of ultrasonic waves that are transmitted through tissue medium. This non-invasive technology shows capacity for a variety of medical applications, including tumor ablation, vascular coagulation, and gene and drug delivery. Nonetheless, there are many problems that can arise from using this technology. The goal of this research was to examine the effectiveness of focused HIFU treatment for prostate cancer by employing an MRI-US fusion platform to pinpoint the precise location of the tumor and administer the therapy. Focal HIFU treatment for locally advanced prostate cancer is a prospective case series employed in this article. There must not be a Gleason 5 signal on the prostatic biopsy and the focal lesion must be less than 20 mm in size on multiparametric Magnetic Resonance Imaging (MRI) for inclusion. The first half of the series were treated with traditional HIFU focused treatment, whereas the second half were treated using an MRI-US fusion platform. Requirement for salvage treatment was used as the major outcome measure of treatment efficacy. Results of supplementary interest were Prostate Specific Antigen (PSA) change, intraoperative morbidity, postoperative clinical outcome, and tumor resurgence in follow-up biopsies.
Anaplastic lymphoma kinase (ALK) is the most common fusion gene involved in non-small cell lung cancer (NSCLC), and remarkable response has been achieved with the use of ALK tyrosine kinase inhibitors (ALK-TKIs). However, the clinical efficacy is highly variable. Pre-existing intratumoral heterogeneity (ITH) has been proven to contribute to the poor treatment response and the resistance to targeted therapies. In this work, we investigated whether the variant allele frequencies (VAFs) of ALK fusions can help assess ITH and predict targeted therapy efficacy. Through the application of next-generation sequencing (NGS), 7.2% (326/4548) of patients were detected to be ALK positive. On the basis of the adjusted VAF (adjVAF, VAF normalization for tumor purity) of four different threshold values (adjVAF < 50%, 40%, 30%, or 20%), the association of ALK subclonality with crizotinib efficacy was assessed. Nonetheless, no statistical association was observed between median progression-free survival (PFS) and ALK subclonality assessed by adjVAF, and a poor correlation of adjVAF with PFS was found among the 85 patients who received first-line crizotinib. Results suggest that the ALK VAF determined by hybrid capture-based NGS is probably unreliable for ITH assessment and targeted therapy efficacy prediction in NSCLC.
