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Expert Rev Anticancer Ther. 2016;16(2):147-57. doi: 10.1586/14737140.2016.1131612. Epub 2016 Jan 4.

Overcoming crizotinib resistance in ALK-rearranged NSCLC with the second-generation ALK-inhibitor ceritinib.

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a Department of Medical Oncology , VU University Medical Center , Amsterdam , The Netherlands.
b Department of Medical Pulmonology , VU University Medical Center , Amsterdam , The Netherlands.
c Cancer Pharmacology Lab , AIRC Start-Up Unit, DIPINT , Pisa , Italy.


In up to 5% of non-small cell lung cancer (NSCLC) patients, the EML4-ALK translocation drives tumor progression. Treatment with the ALK inhibitor crizotinib is more effective than standard chemotherapy. However, resistance to crizotinib occurs after approximately 8 months. Ceritinib is the first second-generation ALK inhibitor approved for treatment of crizotinib-resistant NSCLC. Ceritinib inhibits two of the most common ALK-mutants that confer resistance to crizotinib: L1196 M and G1269A. Cells with ALK expression are more sensitive to ceritinib than crizotinib (IC50 25 nM vs. 150 nM, respectively). Alternative second-generation ALK inhibitors such as Alectinib, Brigatinib and PF-06463922 are currently in development, each affecting different crizotinib-resistant ALK target mutations. Genetic identification of crizotinib-resistant mutants is essential for selecting the optimal treatment strategy in NSCLC patients to overcome resistance and to increase progression-free survival.


Acquired resistance; anaplastic lymphoma kinase; ceritinib; crizotinib; resistance mutation. EML-ALK; tyrosine kinase inhibitors

[Indexed for MEDLINE]

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