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

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.

• Authors: J Cho, S Y Kim, Y J Kim, M H Sim, S T Kim, N K D Kim, K Kim, W Park, J H Kim, K-T Jang, J Lee
• Journal: Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico (Clin Transl Oncol) Vol. 19 Issue 10 Pg. 1247-1252 (Oct 2017) ISSN: 1699-3055 [Electronic] Italy
• PMID: 28421416 (Publication Type: Case Reports, Journal Article)

Chemical References

• CTNNB1 protein, human
• Protein Kinase Inhibitors
• beta Catenin
• Imatinib Mesylate
• Proto-Oncogene Proteins c-kit

Topics

• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (genetics)
• Humans
• Imatinib Mesylate (pharmacology)
• Lung Neoplasms (drug therapy, genetics, secondary)
• Male
• Melanoma (drug therapy, genetics, pathology)
• Middle Aged
• Mutation
• Prognosis
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-kit
• Skin Neoplasms (drug therapy, genetics, secondary)
• Tumor Cells, Cultured
• beta Catenin (genetics)