The role of the ALK receptor in cancer biology

• A vast array of oncogenic variants has been identified for anaplastic lymphoma kinase (ALK). Therefore, there is a need tobetter understand the role of ALK in cancer biology in order to optimise treatment strategies. This review summarises thelatest research on the receptor tyrosine kinase ALK, and how this information can guide the management of patients withcancer that is ALK-positive. A variety of ALK gene alterations have been described across a range of tumour types, includingpoint mutations, deletions and rearrangements. A wide variety of ALK fusions, in which the kinase domain of ALK andthe amino-terminal portion of various protein partners are fused, occur in cancer, with echinoderm microtubule-associatedprotein-like 4 (EML4)-ALK being the most prevalent in non-small-cell lung cancer (NSCLC). Different ALK fusionproteins can mediate different signalling outputs, depending on properties such as subcellular localisation and protein stability. The ALK fusions found in tumours lack spatial and temporal regulation, which can also affect dimerisation and substratespecificity. Two ALK tyrosine kinase inhibitors (TKIs), crizotinib and ceritinib, are currently approved in Europe foruse in ALK-positive NSCLC and several others are in development. These ALK TKIs bind slightly differently within theATP-binding pocket of the ALK kinase domain and are associated with the emergence of different resistance mutationpatterns during therapy. This emphasises the need to tailor the sequence of ALK TKIs according to the ALK signature ofeach patient. Research into the oncogenic functions of ALK, and fast paced development of ALK inhibitors, has substantiallyimproved outcomes for patients with ALK-positive NSCLC. Limited data are available surrounding the physiologicalligand-stimulated activation of ALK signalling and further research is needed. Understanding the role of ALK in tumourbiology is key to further optimising therapeutic strategies for ALK-positive disease. © The Author 2016.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

Anaplastic lymphoma kinase

Ceritinib

Crizotinib

Neuroblastoma

Non-small-cell lung cancer

Tyrosine kinase inhibitor

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