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Lung Cancer (Auckl)
2015 Sep 18;6:71-82. doi: 10.2147/LCTT.S63491.
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First-line treatment of advanced ALK-positive non-small-cell lung cancer.
Gandhi S
,
Chen H
,
Zhao Y
,
Dy GK
.
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Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer deaths, both within the US and worldwide. There have been major treatment advances in NSCLC over the past decade with the discovery of molecular drivers of NSCLC, which has ushered in an era of personalized medicine. There are several actionable genetic aberrations in NSCLC, such as epidermal growth factor receptor and anaplastic lymphoma kinase (ALK). In 3%-7% of NSCLC, a chromosomal inversion event in chromosome 2 leads to fusion of a portion of the ALK gene with the echinoderm microtubule-associated protein-like 4 (EML4) gene. The constitutive activation of the ALK fusion oncogene renders it vulnerable to therapeutic intervention. This review focuses on the first-line treatment of advanced ALK-positive NSCLC using ALK inhibitors. Crizotinib was the first agent proven to be efficacious as first-line treatment for ALK-positive NSCLC. However, acquired resistance inevitably develops. The central nervous system is a sanctuary site that represents a common site for disease progression as well. Hence, more potent, selective next-generation ALK inhibitors that are able to cross the blood-brain barrier have been developed for treatment against crizotinib-resistant ALK-positive NSCLC and are also currently being evaluated for first-line therapy as well. In this review, we provide summary of the clinical experience with these drugs in the treatment of ALK-positive NSCLC.
Figure 1. A chromosomal inversion in chromosome 2 juxtaposes the 5′ end of the EML4 gene with the 3′ end of the ALK gene resulting in the fusion oncogene EML4-ALK.Notes: The resulting chimeric protein, EML4-ALK, contains an N-terminus derived from the EML4 and a C-terminus containing the intracellular tyrosine kinase domain of ALK.Abbreviations: EML4, echinoderm microtubule–associated protein-like 4; ALK, anaplastic lymphoma kinase.
Figure 2. EML4-ALK fusions are due to small inversions within chromosome 2p.Notes: These fusions lead to aberrant expression of ALK and constitutive activation of the ALK tyrosine kinase and further downstream signaling pathways. Hence, this results in uncontrolled proliferation and survival of cancer cells.Abbreviations: EML4, echinoderm microtubule–associated protein-like 4; ALK, anaplastic lymphoma kinase.
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