The gain-of-function mutation D898_E901 RET in medullary thyroid carcinoma (MTC) is sensitive to tyrosine kinase inhibitors, such as selpercatinib and vandetanib, according to a new study published in the Journal of Clinical Oncology Precision Oncology.
Acquired resistance against selpercatinib treatment may develop via RET-independent mechanisms, according to the study authors.
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The team analyzed the oncogenic potential of the mutation and how it responds to treatment with selpercatinib, vandetanib, and cabozantinib in cells grown in the laboratory and in a 35-year-old male, who was harboring the mutation.
Cell culture experiments showed that the mutation led to a higher ligand-independent RET autophosphorylation but similar proliferation rates compared to RET C634R.
When they treated these cells with selpercatinib, the researchers saw that the inhibitory effect of the treatment was similar between the 2 kinds of cells.
However, when they treated them with vandetanib, they found that this was 5-fold less effective in inhibiting cells harboring the D898_E901 RET mutation compared to RET C634R. Similarly, cabozantinib was able to inhibit the proliferation of RET C634R cells but had almost no effect on cells harboring the D898_E901 RET mutation.
The patient had primary resistance to vandetanib and secondary resistance to selpercatinib after a year. Researchers conducted next-generation sequencing on a progressing lesion during treatment with selpercatinib and found no additional RET mutation. However, they identified an acquired mutation that led to the complete loss of the CDKN2A, CDKN2B, and MTAP genes. The patient was then treated with cabozantinib and 5-FU-dacarbazine. However, this was inefficient.
“D898_E901 RET deletion is a gain-of-function mutation and responds to tyrosine kinase inhibitors in MTC. RET Δ898-901 mutant is sensitive to selpercatinib and vandetanib, and acquired resistance to selpercatinib may develop via RET-independent mechanisms,” the researchers concluded.
Porcelli T, Moccia M, De Stefano MA, et al. D898_E901 RET deletion is oncogenic, responds to selpercatinib, and treatment resistance can arise via RET-independent mechanisms. JCO Precis Oncol. Published online August 3, 2023. doi:10.1200/PO.23.00052