D898_E901 RET Deletion Is Oncogenic, Responds to Selpercatinib, and Treatment Resistance Can Arise Via RET-Independent Mechanisms

JCO Precis Oncol. 2023 Aug:7:e2300052. doi: 10.1200/PO.23.00052.

Abstract

Purpose: We analyzed the oncogenic potential of RET Δ898-901 mutant and its response to selpercatinib, vandetanib, and cabozantinib in vitro and in a clinical case.

Materials and methods: A 35-year-old man with a medullary thyroid cancer (MTC) harboring a somatic D898_E901 RET deletion was sequentially treated with vandetanib, selpercatinib, cabozantinib, and fluorouracil (5-FU)-dacarbazine. Functional study of RET Δ898-901 mutant was performed in HEK-293T, NIH-3T3, and Ba/F3 cells. RET C634R and wild-type cells served as positive and negative controls, respectively.

Results: The patient showed primary resistance to vandetanib and secondary resistance to selpercatinib after 12 months. Comprehensive next-generation sequencing of a progressing lesion during selpercatinib showed no additional RET mutation but an acquired complete genetic loss of CDKN2A, CDKN2B, and MTAP genes. Subsequent treatment with cabozantinib and 5-FU-dacarbazine had poor efficacy. In vitro, RET Δ898-901 showed higher ligand-independent RET autophosphorylation compared with RET C634R and similar proliferation rates in cell models. Subcutaneous injection of Δ898-901 NIH 3T3 cells in nude mice produced tumors of around 500 mm3 in 2 weeks, similarly to RET C634R cells. Selpercatinib inhibited cell growth of Ba/F3 RET Δ898-901 and RET C634R with a similar half maximal inhibitory concentration (IC50) of approximately 3 nM. Vandetanib was five-fold less effective at inhibiting cell growth promoted by RET Δ898-901 mutant (IC50, 564 nM) compared with RET C634R one (IC50, 91 nM). Cabozantinib efficiently inhibited Ba/F3 RET C634 proliferation (IC50, 25.9 nM), but was scarcely active in Ba/F3 RET 898-901 (IC50 > 1,350 nM).

Conclusion: 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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dacarbazine / therapeutic use
  • Fluorouracil
  • Humans
  • Mice
  • Mice, Nude
  • Piperidines / therapeutic use
  • Proto-Oncogene Proteins c-ret* / genetics
  • Thyroid Neoplasms* / drug therapy
  • Thyroid Neoplasms* / genetics

Substances

  • cabozantinib
  • selpercatinib
  • Proto-Oncogene Proteins c-ret
  • Piperidines
  • Fluorouracil
  • Dacarbazine
  • RET protein, human

Supplementary concepts

  • Thyroid cancer, medullary