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Emergence of CTNNB1 mutation at acquired resistance to KIT inhibitor in metastatic melanoma

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Abstract

Purpose

The KIT inhibitor, imatinib, has shown promising efficacy in patients with KIT-mutated melanoma; however, acquisition of resistance to imatinib occurs rapidly in the majority of patients. The mechanisms of acquired resistance to imatinib in melanoma remain unclear.

Methods

We analyzed biopsy samples from paired baseline and post-treatment tumor lesions in one patient with KIT-mutated melanoma who had had an initial objective tumor regression in response to imatinib treatment followed by disease progression 8 months later.

Results

Targeted deep sequencing from post-treatment biopsy samples detected an additional mutation in CTNNB1 (S33C) with original KIT L576P mutation. We examined the functional role of the additional CTNNB1 S33C mutation in resistance to imatinib indirectly using the Ba/F3 cell model. Ba/F3 cell lines transfected with both the L576P KIT mutation and the CTNNB1 S33C mutation demonstrated no growth inhibition despite imatinib treatment, whereas growth inhibition was observed in the Ba/F3 cell line transfected with the L576 KIT mutation alone.

Conclusions

We report the first identification of the emergence of a CTNNB1 mutation that can confer acquired resistance to imatinib. Further investigation into the causes of acquired resistance to imatinib will be essential to improve the prognosis for patients with KIT-mutated melanoma.

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Acknowledgements

This work was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C3418).

Author information

Author notes

  1. J. Cho and S. Y. Kim have contributed equally to this work

Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea

    J. Cho, S. Y. Kim, M. H. Sim, S. T. Kim, K. Kim & J. Lee

  2. Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea

    Y. J. Kim

  3. Samsung Genome Institute, Samsung Medical Center, Seoul, Korea

    Y. J. Kim, N. K. D. Kim & W. Park

  4. Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    J. H. Kim

  5. Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    K.-T. Jang

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  1. J. Cho
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Correspondence to J. Lee.

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The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

All procedures performed in studies involving human participants were in accordance with the ethical standards of the local ethics committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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For our retrospective study, formal consent is not required.

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Cho, J., Kim, S.Y., Kim, Y.J. et al. Emergence of CTNNB1 mutation at acquired resistance to KIT inhibitor in metastatic melanoma. Clin Transl Oncol 19, 1247–1252 (2017). https://doi.org/10.1007/s12094-017-1662-x

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  • DOI: https://doi.org/10.1007/s12094-017-1662-x

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