Abstract
Since the discovery of the fusion between EML4 (echinoderm microtubule associated protein-like 4) and ALK (anaplastic lymphoma kinase), EML4-ALK, in lung adenocarcinomas in 2007, and the subsequent identification of at least 15 different variants in lung cancers, there has been a revolution in molecular-targeted therapy that has transformed the outlook for these patients. Our recent focus has been on understanding how and why the expression of particular variants can affect biological and molecular properties of cancer cells, as well as identifying the key signalling pathways triggered, as a result. In the clinical setting, this understanding led to the discovery that the type of variant influences the response of patients to ALK therapy. Here, we discuss what we know so far about the EML4-ALK variants in molecular signalling pathways and what questions remain to be answered. In the longer term, this analysis may uncover ways to specifically treat patients for a better outcome.
Highlights
Lung cancer remains one of the most common types of cancer, accounting for 13% of all cancers diagnosed worldwide [1]
Since the identification of echinoderm microtubule associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) expression in non-small cell lung cancer (NSCLC) patients and the heterogeneous responses observed in terms of sensitivity and time before regression, research focus has shifted in recent years to examine how variants of EML4-ALK correlate to the responses seen
There is a need to generate isogenic lung adenocarcinoma cell lines expressing EML4-ALK variants in order to compare pathways activated in cells with the same genetic background
Summary
Lung cancer remains one of the most common types of cancer, accounting for 13% of all cancers diagnosed worldwide [1]. Genetic analysis has increased our knowledge of the molecular events that lead up to lung cancer, and this has allowed us to identify key driver mutations involved. As a result, both the treatment and outcome of patients has drastically changed in recent years, and molecular screening is a routine procedure for NSCLC. Fusion of EML4 to the kinase domain of ALK results in abnormal signalling and increased cell growth, proliferation, and cell survival. Patients expressing this fusion are treated with an ALK inhibitor such as crizotinib, ceritinib, or alectinib. This review focuses on what we know so far about the EML4-ALK fusion variants and aims to highlight how future research can broaden our understanding, and hopefully lead to better, more personalised therapeutics
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