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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
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Crizotinib (PF02341066) as a ALK /MET inhibitor- Special Emphasis as a Therapeutic Drug Against Lung Cancer
Tobenna Nwizu1, Rajani Kanteti1, Ichiro Kawada1
1Section of Hematology/Oncology, Department of Medicine, University of Chicago.
Abstract:
There are a number of molecular abnormalities that can occur in normal cells to induce a malignant phenotype. Recently, the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) has been shown to have gain-of-function when partnered with different proteins. As an example, on chromosome 2p, with inversion, there is translocation with generation of EML4-ALK tyrosine kinase in lung cancer. In a phase I trial, EML4-ALK patients were selected to determine the response to a potent small molecule tyrosine kinase inhibitor crizotinib (previously identified as PF02341066). Dramatic durable responses were observed with crizotinib at 250 mg twice a day (orally). Interestingly, crizotinib also has activity against MET receptor tyrosine kinase. We have previously shown that MET can be overexpressed, sometimes mutated, or sometimes amplified in lung cancer. Thus, this review will emphasize the characteristics of crizotinib, and detail the clinical experience.
Insights
Crizotinib, a tyrosine kinase inhibitor, showed dramatic responses in lung cancer patients with EML4-ALK fusion proteins. This targeted therapy also demonstrated activity against MET receptor tyrosine kinase.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Malignant transformation involves molecular abnormalities in normal cells.
- Anaplastic lymphoma kinase (ALK) gain-of-function mutations, such as EML4-ALK fusion, drive lung cancer.
- MET receptor tyrosine kinase alterations are implicated in lung cancer development.
Purpose of the Study:
- To review the characteristics and clinical experience of crizotinib.
- To evaluate crizotinib's efficacy in EML4-ALK positive lung cancer.
- To explore crizotinib's activity against MET in lung cancer.
Main Methods:
- Phase I clinical trial.
- Patient selection based on EML4-ALK genetic alterations.
- Administration of crizotinib (PF02341066) orally at 250 mg twice daily.
Main Results:
- Crizotinib demonstrated dramatic and durable responses in EML4-ALK positive lung cancer patients.
- The small molecule tyrosine kinase inhibitor showed significant clinical activity.
- Crizotinib also exhibited activity against the MET receptor tyrosine kinase.
Conclusions:
- Crizotinib is an effective targeted therapy for lung cancer with EML4-ALK fusions.
- The drug's activity against MET warrants further investigation in lung cancer.
- Targeted inhibition of ALK and MET represents a promising therapeutic strategy.
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