Identification of Novel Isoforms of the<i>EML4-ALK</i>Transforming Gene in Non–Small Cell Lung Cancer

Choi, Young Lim; Takeuchi, Kengo; Soda, Manabu; Inamura, Kentaro; Togashi, Yosuke; Hatano, Satoko; Enomoto, Masaya; Hamada, Toru; Higashi, Hidenori; Watanabe, Hideki; Kurashina, Kentaro; Hatanaka, Hisashi; Ueno, Toshihide; Takada, Shuji; Yamashita, Yuichi; Sugiyama, Yukihiko; Ishikawa, Yuichi; Mano, Hiroyuki

doi:10.1158/0008-5472.can-07-6158

Cited by 401 publications

(323 citation statements)

References 19 publications

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“…A number of different EML4-ALK transcript variants have been reported up to date (12,18,(20)(21)(22)(23). The most frequent EML4-ALK variants in NSCLC are E13; A20 (variant 1; ref.…”

Section: Discussionmentioning

confidence: 99%

“…12), and E6a/b; A20 (variant 3; refs. 21,22). A multiplex RT-PCR assay was recently developed for screening all possible in-frame EML4-ALK variants, including the one where EML4 exon 21 is fused to ALK exon 20 (20).…”

Section: Discussionmentioning

confidence: 99%

“…A number of EML4-ALK fusion variants have been identified up to date (12,18,(20)(21)(22)(23); all of them involve an almost identical portion of ALK (exons [20][21][22][23][24][25][26][27][28][29] The constitutive kinase activity of ALK is essential for proliferation of ALCL cells and its inactivation represents a feasible therapeutic approach for the treatment of ALCL (24). The intact ALK kinase domain within EML4-ALK possesses marked transforming as well as oncogenic activity in vitro and in vivo, respectively (12,21,25). Therefore, tumors harboring EML4-ALK fusion seem to represent a distinct subtype that might be responsive to ALK kinase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non–Small Cell Lung Cancers

Lin¹,

Li²,

Guan³

et al. 2009

Molecular Cancer Research

273

190

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The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene has been identified as an oncogene in a subset of non-small cell lung cancers (NSCLC). We used profiling of cancer genomes on an exon array to develop a novel computational method for the global search of gene rearrangements. This approach led to the detection of EML4-ALK fusion in breast and colorectal carcinomas in addition to NSCLC. Screening of a large collection of patient tumor samples showed the presence of EML4-ALK fusion in 2.4% of breast (5 of 209), 2.4% of colorectal (2 of 83), and in 11.3% of NSCLC (12 of 106). Besides previously known EML4-ALK variants 1 (E13; A20) and 2 (E20; A20), a novel variant E21; A20 was found in colorectal carcinoma. The presence of an EML-ALK rearrangement was verified by identifying genomic fusion points in tumor samples representative of breast, colon, and NSCLC. EML4-ALK translocation was also confirmed by fluorescence in situ hybridization assay, which revealed its substantial heterogeneity in both primary tumors and tumor-derived cell lines. To elucidate the functional significance of EML4-ALK, we examined the growth of cell lines harboring the fusion following EML4 and ALK silencing by small interfering RNA. Significant growth inhibition was observed in some but not all cell lines, suggesting their variable dependence on ALK-mediated cell survival signaling. Collectively, these findings show the recurrence of EML4-ALK fusion in multiple solid tumors and further substantiate its role in tumorigenesis. (Mol Cancer Res 2009;7(9):1466-76)

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“…A number of different EML4-ALK transcript variants have been reported up to date (12,18,(20)(21)(22)(23). The most frequent EML4-ALK variants in NSCLC are E13; A20 (variant 1; ref.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non–Small Cell Lung Cancers

Lin¹,

Li²,

Guan³

et al. 2009

Molecular Cancer Research

273

190

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“…153 All seven variants are formed through the fusion of the intracellular tyrosine kinase domain of ALK with a variably truncated EML4 gene. 8,[154][155][156] Activated ALK is involved in the inhibition of apoptosis and the promotion of cellular proliferation through activation of downstream PIK3CA/AKT1-and MAPK1-signaling pathways. 157 Fusion of the EML4-ALK gene and its associated EML4-ALK product may further lead to constitutive activation of the RAS/RAF1/MAP2K1/MAPK1 pathway.…”

Section: Eml4-alk Rearrangement: Driver Mutation Of Lung Cancermentioning

confidence: 99%

Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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The majority of lung adenocarcinoma patients with epidermal growth factor receptor-(EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

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“…When the ALK gene fuses with another gene, it promotes lung cancer cell growth by encoding the production of a tumor-specific protein called anaplastic lymphoma kinase (ALK), an enzyme that is instrumental to cancer cell growth and development. EML4-ALK fusions result from diverse small inversions within the short arm of chromosome 2, with at least nine different variants that have been identified so far [43][44][45].…”

Section: Eml4-alk Fusionmentioning

confidence: 99%

Targetable “Driver” Mutations in Non Small Cell Lung Cancer

Vijayalakshmi

2011

Indian J Surg Oncol

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Lung cancer remains the leading cause of cancerrelated mortality in the world despite advances in the field of cancer therapeutics. Traditional treatment with empirically chosen cytotoxic chemotherapeutic agents, have given small, but real survival benefits. Recent advances and insights into molecular pathogenesis of lung cancers have provided some novel molecular targets, offering newer strategies and agents that are tumor specific. Studies have identified mutations in specific genes that are involved in driving the development of lung cancer and so it is important to subsequently target them with specific drugs thus changing paradigms of management of this type of cancer. Recently, Lung Cancer Mutation Consortium (LCMC) has identified at least one of the many recognized "driver mutations" in nearly two thirds of the patients with advanced cancer. This study suggests that identification of driver mutations can help in molecular targeted therapeutics and in addition supplant tumor histology in guiding treatment decisions, identifying subset of patients who may benefit therapy. This review focuses on these mutations identified in specific genes serving as "drivers" of lung tumorigenesis and suggests that clear promise for the future of lung cancer treatment is indeed personalized therapy with drugs chosen according to the patient mutation profile. Most clinically relevant translational advances made in genes involved in lung tumorigenesis namely EML4-ALK fusions, HER2, PIK3CA, AKT, BRAF, MAP2K1, MET mutations and amplifications along with the well established EGFR and KRAS mutations are discussed in the context of NSCLCs. These studies emphasize the need for treatment management based on mutation profile along with routine histology based classification of these tumors in future for a directed therapy and thus a better therapeutic outcome.

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Identification of Novel Isoforms of theEML4-ALKTransforming Gene in Non–Small Cell Lung Cancer

Cited by 401 publications

References 19 publications

Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non–Small Cell Lung Cancers

Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non–Small Cell Lung Cancers

Molecular pathology of lung cancer: key to personalized medicine

Targetable “Driver” Mutations in Non Small Cell Lung Cancer

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