CUX1-ALK, a Novel ALK Rearrangement That Responds to Crizotinib in Non–Small Cell Lung Cancer

Zhang, Meiling; Wang, Qian; Ding, Yan; Guo-qun, Wang; Chu, Yunqian; He, Xiang; Wu, Xue; Shao, Yang; Lu, Kaihua

doi:10.1016/j.jtho.2018.07.008

Cited by 28 publications

(18 citation statements)

References 12 publications

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“…All variants contain the ALK tyrosine kinase domain and an oligomerization domain in the N-terminal fusion partner gene, which activate downstream pathways to control the proliferation and apoptosis of carcinoma cells. In addition, more non-EML4 fusion variants have been discovered, including kinesin family member 5B (KIF5B) (4), kinesin light-chain 1 (KLC1) (5), cut-like homeobox 1 gene (CUX1) (6). Huntingtininteracting protein 1(H1P1) (7), translocated promoter region (TPR) (8), baculoviral inhibition of apoptosis protein repeatcontaining 6 (BIRC6) (9), and S1 RNA binding domain 1 (SRBD1) (10).…”

Section: Introductionmentioning

confidence: 99%

Prevalence and Clinical Impact of Concomitant Mutations in Anaplastic Lymphoma Kinase Rearrangement Advanced Non-small-Cell Lung Cancer (Guangdong Association of Thoracic Oncology Study 1055)

Hou

Zhou

et al. 2020

Front. Oncol.

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Background: In patients with anaplastic lymphoma kinase (ALK) rearrangement-positive advanced non-small-cell lung cancer (NSCLC), ALK inhibitors are now the standard treatment, but their clinical efficacy varies widely for each patient. In this multicenter retrospective study, we evaluated the clinical efficacy of crizotinib according to the ALK rearrangement variants and concomitant mutations present. Patients and Methods: A total 132 patients with ALK rearrangement advanced NSCLC from 4 centers in Guangdong province, China were evaluated. All patients received crizotinib treatment and their ALK rearrangement status was identified by next-generation sequencing (NGS). Results: The median progression-free survival (PFS) in patients with EML4-ALK rearrangement (n = 121), non-EML4-ALK rearrangement (n = 5), and EML4-ALK arrangement accompanied by non-EML4-ALK rearrangement (n = 6) was 12.8, 7.5, and 7.4 months, respectively, with no significant difference between them (p = 0.1554). Similarly, among patients with various EML4-ALK variants (variant 1, variant 3a/b, and other variants), the median PFS values were again comparable. According to baseline NGS data, the median PFS in patients who had ALK rearrangement only, ALK rearrangement and concomitant tumor-suppressor gene mutations, and ALK rearrangement and concomitant oncogene mutations was 14.2, 10.9, and 4.9 months, respectively; (p = 0.0002). A multivariable analysis indicated that concomitant oncogene mutations and tumor-suppressor gene mutations were both negative factors influencing the efficacy of crizotinib in ALK rearrangement NSCLC. Li et al. Concomitant Mutations in ALK Rearrangement NSCLC Conclusion: Concomitant oncogene mutations and tumor-suppressor gene mutations had negative effects on the efficacy of crizotinib, while various ALK variants had a similar influence.

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Section: Introductionmentioning

confidence: 99%

Prevalence and Clinical Impact of Concomitant Mutations in Anaplastic Lymphoma Kinase Rearrangement Advanced Non-small-Cell Lung Cancer (Guangdong Association of Thoracic Oncology Study 1055)

Hou

Zhou

et al. 2020

Front. Oncol.

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“…Ever since the discovery of the transforming EML4-ALK fusion gene by Soda and Rikova et al in 2007, various ALK fusion partners have been identified including TFG , KIF5B , KCL1 , PTPN3 , STRN , HIP1 , TPR , BIRC6 , DCTN1 , SQSTM1 , SOCS5 , CLIP4 , CLTC , PRKAR1A , PPM1B , EIF2AK3 , CRIM1 , GCC2 , DYSF , ITGAV , VIT , PLEKHA7 , and CUX1 . 1 – 19 A list of chronologically published fusion partners in ALK -rearranged lung cancer with references is summarized in Table 1 . The VKORC1L1 gene encodes an enzyme known as vitamin K 2,3-epoxide reductase, whose catalytic function is critical for the vitamin K cycle.…”

Section: Discussionmentioning

confidence: 99%

Dramatic response to alectinib in a lung cancer patient with a novel <em>VKORC1L1-ALK</em> fusion and an acquired ALK T1151K mutation

Zhu¹,

Schrock²,

Bosemani³

et al. 2018

LCTT

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ALK-rearranged lung cancer defines a distinctive molecular cohort of patients whose outcomes are significantly improved by the availability of ALK inhibitors. Thus, it is imperative for clinicians to screen appropriate patients for this driver mutation with a molecular testing platform capable of capturing all ALK fusions. Here, we report a novel VKORC1L1-ALK fusion and an ALK T1151K resistance mutation detected in a lung cancer patient who had been on crizotinib for over 8 years. Alectinib induced a dramatic response in this patient demonstrating its clinical activity against T1151K. This case illustrates the importance of performing repeat biopsy to explore mechanism(s) of resistance when patients experience disease progression on an ALK inhibitor. The approach has a direct therapeutic impact particularly when an ALK resistance mutation is identified.

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“…KIF5B (kinesin family member 5B), CUX1 (cut-like homeobox 1) (ref. 20 ), STRN (striatin) (ref. 21 ), DCTN1 (dynactin-1), SQSTM1 (sequestome-1) (ref.…”

Section: Clinical Biomarkers Currently Used In Therapeutic Strategiesmentioning

confidence: 99%

“…With the introduction of NGS to molecular genetics and molecular diagnostics by allowing formalin-fixed paraffin embedded (FFPE) tissues to be screened, there are new efficiency and time duration options available. This technology is being introduced at new laboratories requiring accurate and timely results which guide patient therapy decisions [20][21][22][55][56][57][58] . NGS for SNVs, INDELs and CNVs detection is based on DNA sequencing, in contrast to RNA-seq developed mainly for detection of gene fusions.…”

Section: Next-generation Sequencingmentioning

confidence: 99%

Gene rearrangement detection by next-generation sequencing in patients with non-small cell lung carcinoma

Brisudova¹,

Škarda²

2020

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related deaths worldwide. Various molecular markers in NSCLC patients have been developed, including gene rearrangements, currently used in therapeutic strategies. With increasing number of these molecular biomarkers of NSCLC, there is a demand for highly efficient methods for detecting mutations and translocations in treatable targets. Those currently available U.S. Food and Drug Administration (FDA) approved approaches, for example imunohistochemisty (IHC) and fluorescence in situ hybridization (FISH), are inadequate, due to sufficient quantity of material and long time duration. Next-generation massive parallel sequencing (NGS), with the ability to perform and capture data from millions of sequencing reactions simultaneously could resolve the problem. Thanks to gradual NGS introduction into clinical laboratories, screening time should be considerably shorter, which is very important for patients with advanced NSCLC. Moreover, only a minimum sample input is needed for achieving adequate results. NGS was compared to the current detection methods of ALK, ROS1, c-RET and c-MET rearrangements in NSCLC and a significant match, between IHC, FISH and NGS results, was found. Recent available researches have been carried out on a small numbers of patients. Verifying these results on larger patients cohort is important. This review sumarizes the literature on this subject and compares current possibilities of predictive gene rearrangements detection in patients with NSCLC.

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CUX1-ALK, a Novel ALK Rearrangement That Responds to Crizotinib in Non–Small Cell Lung Cancer

Abstract: This study provides the novel finding of a CUX1-ALK fusion gene from a patient with NSCLC that could provide personalized treatment solutions for the maximum benefit to patients with NSCLC.

Cited by 28 publications

References 12 publications

Prevalence and Clinical Impact of Concomitant Mutations in Anaplastic Lymphoma Kinase Rearrangement Advanced Non-small-Cell Lung Cancer (Guangdong Association of Thoracic Oncology Study 1055)

Prevalence and Clinical Impact of Concomitant Mutations in Anaplastic Lymphoma Kinase Rearrangement Advanced Non-small-Cell Lung Cancer (Guangdong Association of Thoracic Oncology Study 1055)

Dramatic response to alectinib in a lung cancer patient with a novel <em>VKORC1L1-ALK</em> fusion and an acquired ALK T1151K mutation

Gene rearrangement detection by next-generation sequencing in patients with non-small cell lung carcinoma

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