Fusion variants of the ALK gene — the key to modern therapy for patients with ALK-positive non-small-cell lung cancer
Abstract
Since the discovery of the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion in non-small-cell lung cancer (NSCLC), followed by the identification of many different fusion variants, molecularly targeted therapy has revolutionized treatment for patients with ALK-positive lung cancer. Recent research has focused on understanding how specific variants may influence the biological and molecular behavior of cancer cells and how this knowledge can be used in routine clinical practice. This article explores the current understanding of EML4-ALK variants and highlights unanswered questions in the field.
Keywords: EML4-ALK Variant 1EML4-ALK Variant 2EML4-ALK Variant 3NSCLC
References
- Soda M, Choi Y, Enomoto M, et al. Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer. Nature. 2007; 448(7153): 561–566.
- Horn L, Pao W. EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol. 2009; 27(26): 4232–4235.
- Lin YT, Liu YN, Shih JY. The Impact of Clinical Factors, ALK Fusion Variants, and BIM Polymorphism on Crizotinib-Treated Advanced EML4-ALK Rearranged Non-small Cell Lung Cancer. Front Oncol. 2019; 9: 880.
- Mitiushkina NV, Tiurin VI, Iyevleva AG, et al. Variability in lung cancer response to ALK inhibitors cannot be explained by the diversity of ALK fusion variants. Biochimie. 2018; 154: 19–24.
- Kwak E, Bang YJ, Camidge D, et al. Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer. N Engl J Med. 2010; 363(18): 1693–1703.
- Gaughan EM, Costa DB. Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities. Ther Adv Med Oncol. 2011; 3(3): 113–125.
- Ou SHI, Bartlett CH, Mino-Kenudson M, et al. Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology. Oncologist. 2012; 17(11): 1351–1375.
- Ali SM, Hensing T, Schrock AB, et al. Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization. Oncologist. 2016; 21(6): 762–770.
- Zheng D, Wang R, Zhang Y, et al. Prevalence and clinicopathological characteristics of ALK fusion subtypes in lung adenocarcinomas from Chinese populations. J Cancer Res Clin Oncol. 2016; 142(4): 833–843.
- Wen S, Dai L, Wang L, et al. Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer. Oncologist. 2019; 24(11): e1070–e1081.
- Zhou X, Shou J, Sheng J, et al. Molecular and clinical analysis of Chinese patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer. Cancer Sci. 2019; 110(10): 3382–3390.
- Du X, Shao Y, Qin HF, et al. ALK-rearrangement in non-small-cell lung cancer (NSCLC). Thorac Cancer. 2018; 9(4): 423–430.
- Sabir SR, Yeoh S, Jackson G, et al. EML4-ALK Variants: Biological and Molecular Properties, and the Implications for Patients. Cancers (Basel). 2017; 9(9).
- Sasaki T, Rodig SJ, Chirieac LR, et al. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 2010; 46(10): 1773–1780.
- Yoshida T, Oya Y, Tanaka K, et al. Differential Crizotinib Response Duration Among ALK Fusion Variants in ALK-Positive Non-Small-Cell Lung Cancer. J Clin Oncol. 2016; 34(28): 3383–3389.
- Richards MW, Law EWP, Rennalls LP, et al. Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain. Proc Natl Acad Sci U S A. 2014; 111(14): 5195–5200.
- Heuckmann JM, Balke-Want H, Malchers F, et al. Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants. Clin Cancer Res. 2012; 18(17): 4682–4690.
- Solomon BJ, Mok T, Kim DW, et al. PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014; 371(23): 2167–2177.
- Soria JC, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017; 389(10072): 917–929.
- Peters S, Camidge DR, Shaw AT, et al. ALEX Trial Investigators. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017; 377(9): 829–838.
- Camidge D, Kim H, Ahn MJ, et al. Brigatinib Versus Crizotinib in Advanced ALK Inhibitor–Naive ALK-Positive Non–Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial. J Clin Oncol. 2020; 38(31): 3592–3603.
- Selvaggi G, Wakelee HA, Mok T, et al. ID:1882 Phase III Randomized Study of Ensartinib vs Crizotinib in Anaplastic Lymphoma Kinase (ALK) POSITIVE NSCLC Patients: eXalt3. J Thorac Oncol. 2020; 15(10): e41–e42.
- Shaw AT, Bauer TM, de Marinis F, et al. CROWN Trial Investigators. First-Line Lorlatinib or Crizotinib in Advanced -Positive Lung Cancer. N Engl J Med. 2020; 383(21): 2018–2029.
- Camidge D, Dziadziuszko R, Peters S, et al. Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non–Small Cell Lung Cancer in the Global Phase III ALEX Study. J Thorac Oncol. 2019; 14(7): 1233–1243.
- Camidge D, Niu H, Kim H, et al. Correlation of baseline molecular and clinical variables with ALK inhibitor efficacy in ALTA-1L. J Clin Oncol. 2020; 38(15_suppl): 9517–9517.
- Christopoulos P, Endris V, Bozorgmehr F, et al. EML4-ALK fusion variant V3 is a high-risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK non-small cell lung cancer. Int J Cancer. 2018; 142(12): 2589–2598.
- Qin K, Hou H, Liang Yu, et al. Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis. BMC Cancer. 2020; 20(1): 328.
- Song P, Zhang F, Li Y, et al. Concomitant TP53 mutations with response to crizotinib treatment in patients with ALK‐rearranged non‐small‐cell lung cancer. Cancer Medicine. 2019; 8(4): 1551–1557.
- Tao H, Shi L, Zhou A, et al. Distribution of EML4-ALK fusion variants and clinical outcomes in patients with resected non-small cell lung cancer. Lung Cancer. 2020; 149: 154–161.