title: ALK and ROS1 as targeted therapy paradigms and clinical implications to overcome crizotinib resistance.
abstract: During the past decade, more than 10 targetable oncogenic driver genes have been validated in non-small cell lung cancer (NSCLC). Anaplastic lymphoma kinase (ALK) and ROS1 kinase are two new driver genes implicated in ALK- and ROS1-rearranged NSCLC. Inhibition of ALK and ROS1 by crizotinib has been reported to be highly effective and well tolerated in these patients. However, resistance to crizotinib emerges years after treatment, and increasing efforts have been made to overcome this issue. Here, we review the biology of ALK and ROS1 and their roles in cancer progression. We also summarize the ongoing and completed clinical trials validating ALK and ROS1 as targets for cancer treatment. In the last section of the review, we will discuss the molecular mechanisms of crizotinib resistance and focus approaches to overcome it. This review describes an exciting new area of research and may provide new insights for targeted cancer therapies.
authors.affiliation: Department of Pulmonary Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Mingxiang
authors.initials: M
authors.lastname: Ye
authors.affiliation: Department of Pulmonary Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pulmonary Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Pulmonary Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Pengyu
authors.initials: P
authors.lastname: Jing
authors.affiliation: Department of Pulmonary Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Chang
authors.affiliation: Department of Pulmonary Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pulmonary Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Xinling
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Pulmonary Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases
keywords: ROS1 kinase; anaplastic lymphoma kinase; crizotinib; drug resistance; non-small cell lung cancer