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Acquired Resistance to Crizotinib in NSCLC with MET Exon 14 Skipping
Rebecca S Heist1, Lecia V Sequist1, Darrell Borger2
1Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
Introduction:
MET proto-oncogene, receptor tyrosine kinase gene (MET) exon 14 skipping is a targetable alteration in lung cancer. Treatment with MET proto-oncogene, receptor tyrosine kinase inhibitor can cause dramatic responses in patients whose cancers have MET exon 14 skipping. Little is known, however, about acquired resistance in patients with MET exon 14 skipping.
Methods:
Biopsy specimens obtained at baseline and at the time of progression for a patient being treated with crizotinib were compared using targeted next-generation sequencing to assess for mechanisms of resistance.
Results:
An acquired mutation in the MET kinase domain, D1228N, was found at time of progression on crizotinib in a patient with MET exon 14 skipping.
Conclusions:
One potential mechanism of acquired resistance to crizotinib in patients with MET exon 14 skipping is through second-site mutations in the MET gene. Understanding mechanisms of resistance will be important in optimizing therapy in these patients.
Insights
MET exon 14 skipping lung cancers respond to targeted inhibitors. However, acquired resistance can occur, as seen with a new MET kinase domain mutation (D1228N) in one patient.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MET exon 14 skipping alterations are targetable in lung cancer.
- MET inhibitors yield significant responses in patients with MET exon 14 skipping.
- Mechanisms of acquired resistance to MET inhibitors are not well understood.
Purpose of the Study:
- To investigate acquired resistance mechanisms in lung cancer patients with MET exon 14 skipping treated with MET inhibitors.
- To identify specific genetic alterations conferring resistance to MET-targeted therapy.
Main Methods:
- Targeted next-generation sequencing was employed.
- Comparison of biopsy specimens from baseline and progression during crizotinib treatment.
- Assessment for resistance mechanisms in a patient with MET exon 14 skipping.
Main Results:
- A patient with MET exon 14 skipping developed acquired resistance to crizotinib.
- An acquired mutation, D1228N, in the MET kinase domain was identified at progression.
- This mutation represents a potential mechanism of resistance.
Conclusions:
- Second-site mutations in the MET gene, such as D1228N, are a potential mechanism of acquired resistance to crizotinib in MET exon 14 skipping lung cancer.
- Understanding these resistance mechanisms is crucial for optimizing future therapeutic strategies.
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