Title:A Pan-Cancer Review of ALK Mutations: Implications for Carcinogenesis and Therapy
Volume: 15
Issue: 4
Author(s): Nick Ka Ming Yau, Andrew Yuon Fong, Hiu Fung Leung, Krista Roberta Verhoeft and Qin Ying Lim, Wai Yip Lam, Ian Chi Kei Wong and Vivian Wai Yan Lui
Affiliation:
关键词:
获得性耐药，ALK抑制剂敏感性，ALK基因突变，致癌基因的活化。
摘要: 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.
