A Pan-Cancer Review of ALK Mutations: Implications for Carcinogenesis and Therapy
[ Vol. 15 , Issue. 4 ]
Nick Ka Ming Yau, Andrew Yuon Fong, Hiu Fung Leung, Krista Roberta Verhoeft, Qin Ying Lim, Wai Yip Lam, Ian Chi Kei Wong and Vivian Wai Yan LuiPages 327-336 (10)
The anaplastic lymphoma kinase (ALK) is a druggable target for cancer therapy. By and large, the oncogenic activation of ALK in human tumors is known to occur by gene rearrangement (e.g. EML4-ALK, NMP-ALK
, etc.). Clinical use of ALK inhibitors for “ALK
-rearranged” lung cancers has remarkably improved patient survival. To date, much has been known about ALK gene rearrangement in human carcinogenesis and its drug sensitivity relationship. However, emerging genomic data from the Cancer Genome Atlas (TCGA, USA) are now revealing common ALK
point mutations (~3.06%) in various cancer types other than lung cancer. Importantly, several recent studies have demonstrated that ALK point mutations, independent of ALK
-gene rearrangement, can be oncogenic. Thus, ALK
mutations can be pathogenically and perhaps therapeutically important for various cancer types. Here, we summarized the latest ALK
mutation frequencies and mutation patterns across 17 human cancer types stemming from TCGA. Unlike many other oncogenes with high frequency of hotspot mutations, ALK
point mutations tend to span along the entire gene. Up till now, several recurrent mutations (G263, R401, R551, P968 and E1242) and mutation-rich cluster regions have been identified, but their functional effects remain unknown. We also conducted a comprehensive review of all ALK
-mutated human cancer cell lines (from the Cell Line Encyclopedia (CCLE) and the NCI-60 panel), which can be used as model systems for ALK
mutation biology and drug screening studies. Lastly, we summarized both the preclinical and clinical findings of ALK
mutations on carcinogenesis and drug sensitivity, which may provide important insight into new treatment strategies and prompt future ALK
mutation studies in various cancer types.
Acquired resistance, ALK inhibitor sensitivity, ALK mutations, oncogenic activation.
Department of Pharmacology and Pharmacy, L2-54, Laboratory Block, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong.
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