Abstract
Background
Targeting of somatic MET mutations using crizotinib has led to strong clinical responses, most frequently
in patients with lung cancer, raising the possibility of adopting similar treatment
strategies in patients with MET alterations in other cancer types.
Patient and Methods
We describe a patient with advanced triple-negative breast cancer with a 30-fold amplification
of MET. Next-generation sequencing of pre- and postprogression biopsies was performed to
identify the resistance mechanism emerging after an initial exceptional response to
crizotinib. The response of the resistance mutant to type I and II MET inhibitors
was assessed in cultured cells.
Results
After progressing on crizotinib, a MET-D1228N mutation was detected, which is located
in the crizotinib-binding region of the MET kinase domain. Experimental studies demonstrated
that this mutation confers complete resistance to crizotinib yet retains cabozantinib
sensitivity. Treatment of the patient with cabozantinib led to a subjective improvement
in clinical symptoms, but the patient progressed after 7 weeks.
Conclusion
Although MET mutations are rare in breast cancer, these patients may experience substantial clinical
benefit from crizotinib treatment. Nevertheless, drug resistance owing to on-target
MET mutations will likely be frequently encountered and comprehensive mechanistic studies
to assess sensitivity of these mutants to a series of potential second-line therapies
may help guide subsequent treatment for these patients.
Keywords
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Article info
Publication history
Published online: February 19, 2020
Accepted:
February 10,
2020
Received in revised form:
January 27,
2020
Received:
December 3,
2019
Identification
Copyright
© 2020 Elsevier Inc. All rights reserved.
