Anaplastic Lymphoma Kinase as a Therapeutic Target in Non-Small Cell Lung Cancer
Wade T Iams1, Christine M Lovly
1From the Departments of *Medicine and †Cancer Biology, Vanderbilt University Medical Center, and ‡Vanderbilt-Ingram Cancer Center, Nashville, TN.
Abstract:
The therapeutic targeting of anaplastic lymphoma kinase (ALK) has been a burgeoning area of research since 2007 when ALK fusions were initially identified in patients with non-small cell lung cancer. The field has rapidly progressed through development of the first-generation ALK inhibitor, crizotinib, to an understanding of mechanisms of acquired resistance to crizotinib and is currently witnessing an explosion in the development of next-generation ALK inhibitors such as ceritinib, alectinib, PF-06463922, AP26113, X-396, and TSR-011. As with most targeted therapies, acquired resistance appears to be an inevitable outcome. Current preclinical and clinical studies are focused on the development of rational therapeutic strategies, including novel ALK inhibitors, as well as rational combination therapies to maximize disease control by delaying or overcoming acquired therapeutic resistance. This review summarizes the existing clinical data and ongoing research pertaining to the clinical application of ALK inhibitors in patients with non-small cell lung cancer.
Insights
Targeting anaplastic lymphoma kinase (ALK) with inhibitors is crucial for non-small cell lung cancer. Research focuses on overcoming acquired resistance with next-generation ALK inhibitors and combination therapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Anaplastic lymphoma kinase (ALK) fusions were first identified in non-small cell lung cancer (NSCLC) in 2007.
- Targeting ALK has become a significant area of research for NSCLC treatment.
- Acquired resistance to targeted therapies is a common challenge.
Purpose of the Study:
- To review the clinical data and ongoing research on ALK inhibitors in NSCLC.
- To summarize the progression from first-generation to next-generation ALK inhibitors.
- To discuss strategies for overcoming acquired resistance to ALK-targeted therapies.
Main Methods:
- Review of existing clinical trial data.
- Summary of preclinical studies on resistance mechanisms.
- Analysis of ongoing research into novel ALK inhibitors and combination therapies.
Main Results:
- Development of first-generation ALK inhibitor (crizotinib).
- Identification of mechanisms of acquired resistance to crizotinib.
- Emergence of multiple next-generation ALK inhibitors (e.g., ceritinib, alectinib).
Conclusions:
- Acquired resistance to ALK inhibitors is an expected outcome in NSCLC treatment.
- Novel ALK inhibitors and combination therapies are being developed to address resistance.
- Maximizing disease control requires strategies to delay or overcome acquired therapeutic resistance.
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