Drug resistance in ALK-positiveNon-small cell lungcancer patients.
Patients are diagnosed as anaplastic lymphoma kinase (ALK) positive, i.e. exhibiting the ALK rearrangement, and comprise 3-7% of non-small-cell lung cancer (NSCLC) cases. Three generations of ALK inhibitors have been developed and used in targeted therapy, although there are still improving spaces of drug resistance at the initiation of each treatment. The current review discusses the pathophysiology of ALK-positive NSCLC and the role of three generations of ALK target inhibitors including crizotinib, ceritinib, alectinib and lorlatinib, as well as the mechanisms of the secondary resistance. We mainly focused on the point mutations that are the most important resistance-producing mechanism and most common form caused by each inhibitor. In addition, we examine the three-dimensional structure of ALK to understand the functional impact of these mutations and analyse the underlying molecular mechanisms of the resistance to each generation of ALK inhibitor to benefit the selection decision of the most rational therapy and improve therapeutic effects to the disease.
Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai Institute of Clinical Bioinformatics, Biomedical Research Center, Shanghai, China.
Mengjia
M
Qian
Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai Institute of Clinical Bioinformatics, Biomedical Research Center, Shanghai, China.
Bijun
B
Zhu
Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai Institute of Clinical Bioinformatics, Biomedical Research Center, Shanghai, China. Electronic address: xiangdong.wang@clintransmed.org.
Xiangdong
X
Wang
Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai Institute of Clinical Bioinformatics, Biomedical Research Center, Shanghai, China. Electronic address: michael.liebman@ipqanalytics.com.
Michael
M
Liebman
D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D017354:Point Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
ALK; Alectinib; Ceritinib; Crizotinib; Lorlatinib; Point mutation