ALK and ROS1 as targeted therapy paradigms and clinical implications to overcome crizotinib resistance

Mingxiang Ye; Xinxin Zhang; Nan Li; Yong Zhang; Pengyu Jing; Ning Chang; Jianxiong Wu; Xinling Ren; Jian Zhang

doi:10.18632/oncotarget.6935

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ALK and ROS1 as targeted therapy paradigms and clinical implications to overcome crizotinib resistance

Mingxiang Ye, Xinxin Zhang, Nan Li, Yong Zhang, Pengyu Jing, Ning Chang, Jianxiong Wu, Xinling Ren and Jian Zhang _

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Oncotarget. 2016; 7:12289-12304. https://doi.org/10.18632/oncotarget.6935

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Abstract

Mingxiang Ye1,*, Xinxin Zhang1,*, Nan Li1, Yong Zhang1, Pengyu Jing2, Ning Chang1, Jianxiong Wu1, Xinling Ren1 and Jian Zhang1

1 Department of Pulmonary Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, China

2 Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, China

* These authors contributed equally to this work

Correspondence to:

Jian Zhang, email:

Keywords: non-small cell lung cancer; anaplastic lymphoma kinase; ROS1 kinase; crizotinib; drug resistance

Received: August 14, 2015 Accepted: January 12, 2016 Published: January 18, 2016

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.

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ALK and ROS1 as targeted therapy paradigms and clinical implications to overcome crizotinib resistance

Abstract