What is it about?

DNA rearrangements can cause cancer. The ALK gene can rearrange in some tumors, when it gets cut and pasted onto a different chromosome, next to another gene, resulting in a gene fusion. The new fused gene is called NPM-ALK in a rare type of lymphoma and EML4-ALK in few cases of lung cancer, because ALK jumps next to NPM or EML4 gene, respectively. These “chimeric” genes make the cells proliferate faster in uncontrolled manner, causing the disease. Fortunately, there are medicines that can block the enzyme encoded by ALK fusions, killing cancer cells. However, in many cases, new mutated forms of ALK are generated, that are insensitive to the drugs and cause a tumor relapse. We focused our attention on these two types of ALK fusion, trying to understand their sensitivity to drugs when they are mutated.

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Why is it important?

Our work provided a classification of the various mutants according to their level of sensitivity/resistance to the drugs. Our data revealed that most mutants can be targeted by using different inhibitors. One relevant exception is represented by the G1202R mutation, which is highly resistant to all drugs and represents the most challenging mutation to overcome.


These results provide a prediction of cross-resistance of known drug-resistant mutations against all second generation inhibitors clinically available, and therefore could be a useful tool to help clinicians in the management of crizotinib-resistance cases.

Luca Mologni
Universita degli Studi di Milano-Bicocca

Read the Original

This page is a summary of: Activity of second-generation ALK inhibitors against crizotinib-resistant mutants in an NPM-ALK model compared to EML4-ALK, Cancer Medicine, February 2015, Wiley, DOI: 10.1002/cam4.413.
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