EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer
By J. Koivunen, Craig H. Mermel, K. Zejnullahu, C. Murphy, E. Lifshits, A. Holmes, H. Choi, Jhingook Kim, Derek Y. Chiang, Roman K. Thomas and 11 more. Clinical Cancer Research, 2008
1,002 citations recorded by the source corpus.
Purpose: The EML4-ALK fusion gene has been detected in ∼7% of Japanese non-small cell lung cancers (NSCLC). We determined the frequency of EML4-ALK in Caucasian NSCLC and in NSCLC cell lines. We also determined whether TAE684, a specific ALK kinase inhibitor, would inhibit the growth of EML4-ALK-containing cell lines in vitro and in vivo. Experimental Design: We screened 305 primary NSCLC [both U.S. (n = 138) and Korean (n = 167) patients] and 83 NSCLC cell lines using reverse transcription-PCR and by exon array analyses. We evaluated the efficacy of TAE684 against NSCLC cell lines in vitro and in vivo. Results: We detected four different variants, including two novel variants, of EML4-ALK using reverse transcription-PCR in 8 of 305 tumors (3%) and 3 of 83 (3.6%) NSCLC cell lines. All EML4-ALK-containing tumors and cell lines were adenocarcinomas. EML4-ALK was detected more frequently in NSCLC patients who were never or light (<10 pack-years) cigarette smokers compared with current/former smokers (6% versus 1%; P = 0.049). TAE684 inhibited the growth of one of three (H3122) EML4-ALK-containing cell lines in vitro and in vivo, inhibited Akt phosphorylation, and caused apoptosis. In another EML4-ALK cell line, DFCI032, TAE684 was ineffective due to coactivation of epidermal growth factor receptor and ERBB2. The combination of TAE684 and CL-387,785 (epidermal growth factor receptor/ERBB2 kinase inhibitor) inhibited growth and Akt phosphorylation and led to apoptosis in the DFCI032 cell line. Conclusions:EML4-ALK is found in the minority of NSCLC. ALK kinase inhibitors alone or in combination may nevertheless be clinically effective treatments for NSCLC patients whose tumors contain EML4-ALK.
Subfields: Cell Biology, Oncology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/f1a57df5d3599af0426a407b2b19e9b78b83aad7
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Citations in the corpus
- Non-small cell lung cancer: current treatment and future advances. (2016, background): “Approximately 3–7% of all lung tumors contain ALK mutations (56-58) where these mutations are commonly seen in patients who are of a younger age.”
- The EML4‐ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild‐type EGFR and KRAS (2009, background): “Data from other series also indicated more frequent involvement in nonsmokers.(12,13,15) Because AD is the most common tumor type in both smokers and nonsmokers, we analyzed the AD subgroup, but the association became nonsignificant (P1⁄4 .”
- Haplotyping germline and cancer genomes using high-throughput linked-read sequencing (2016, neutral): “The lung cancer cell line NCI-H2228 contains an EML4/ALK fusion 24, 25 in which exons 1–6 of EML4 are fused to exons 20–29 of ALK.”
- Brigatinib versus Crizotinib in ALK‐Positive Non–Small‐Cell Lung Cancer (2018, neutral): “Decreased appetite 10 (7) 1 (1) 27 (20) 4 (3)”
- Unique Clinicopathologic Features Characterize ALK-rearranged Lung Adenocarcinoma in the Western Population (2009, background): “13 Positive 6 (30) 81 (24) Not evaluated 10 (50) 81 (24) Stage,* n (%) I 4 (15) 165 (49) 0.”
- Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases. (2015, background): “Tumors with ALK rearrangements are addicted to ALK signaling and are inhibited by ALK TKIs in preclinical models.(9,13-15) JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T”
- Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. (2009, background): “7% in unselected populations.(7,11,13-17) These studies have involved predominantly Asian patients with surgically resected disease.”