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

Oncotarget
Mingxiang YeJian Zhang

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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Methods Mentioned

BETA
PCR
biopsy
xenograft
xenografts

Clinical Trials Mentioned

NCT01121575
NCT00585195
NCT00932451
NCT00932893
NCT01154140
NCT01639001
NCT01449461
NCT01283516
NCT01970865
NCT01579994

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