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Review
. 2016 Mar 15;7(11):12289-304.
doi: 10.18632/oncotarget.6935.

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

Mingxiang Ye  1 , Xinxin Zhang  1 , Nan Li  1 , Yong Zhang  1 , Pengyu Jing  2 , Ning Chang  1 , Jianxiong Wu  1 , Xinling Ren  1 , Jian Zhang  1
Affiliations
Review

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

Mingxiang Ye et al. Oncotarget. .

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.

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

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Conflict of interest statement

CONFLICTS OF INTEREST

This review was sponsored by grants from the National Natural Science Foundation of China (#81272518 and #81472192 to Jian Zhang). The authors have no other relevant affiliations or financial involvements with any organization or entity with a financial interest in or a financial conflict with the subject matter or materials discussed in the manuscript.

Figures

Figure 1
Figure 1. The signaling pathway and the molecular actions of crizotinib on EML4-ALK variant 1 fusion protein
A. The EML4-ALK variant 1 fusion protein constitutively activates PI3K/Akt, MAPK/Erk and Jak/Stat signaling, which promotes cell proliferation, survival and tumorigenesis. B. The ALK inhibitor crizotinib inhibits the kinase activity of EML4-ALK variant 1 and subsequently abrogates the downstream PI3K/Akt, MAPK/Erk and Jak/Stat signaling, leading to cancer cell apoptosis and death.
Figure 1
Figure 1. The signaling pathway and the molecular actions of crizotinib on EML4-ALK variant 1 fusion protein
A. The EML4-ALK variant 1 fusion protein constitutively activates PI3K/Akt, MAPK/Erk and Jak/Stat signaling, which promotes cell proliferation, survival and tumorigenesis. B. The ALK inhibitor crizotinib inhibits the kinase activity of EML4-ALK variant 1 and subsequently abrogates the downstream PI3K/Akt, MAPK/Erk and Jak/Stat signaling, leading to cancer cell apoptosis and death.
Figure 2
Figure 2. The molecular machinery responsible for crizotinib resistance
A. The presence of “gatekeeper” L1196M resistance mutation hinders crizotinib binding to the ATP binding domain of ALK kinase, which sustains the downstream PI3K/Akt, MAPK/Erk and Jak/Stat signaling in the presence of crizotinib. B. The activation of bypass EGFR and c-kit pathway rescues the PI3K/Akt, MAPK/Erk and Jak/Stat signaling, downstream of EML4-ALK variant 1 fusion protein.
Figure 2
Figure 2. The molecular machinery responsible for crizotinib resistance
A. The presence of “gatekeeper” L1196M resistance mutation hinders crizotinib binding to the ATP binding domain of ALK kinase, which sustains the downstream PI3K/Akt, MAPK/Erk and Jak/Stat signaling in the presence of crizotinib. B. The activation of bypass EGFR and c-kit pathway rescues the PI3K/Akt, MAPK/Erk and Jak/Stat signaling, downstream of EML4-ALK variant 1 fusion protein.
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