Gene expression changes in response to acute and chronic in vitro treatment with selpercatinib and pralsetinib in a murine Trim24-Ret cell line, TR.1

The TKIs selpercatinib and pralsetinib represent first line therapies for RET-positive lung cancer patients. Most patients exhibit responses, but treatment failure eventually occurs. To study acquired resistance in RET+ lung cancer, a novel murine lung cancer cell line was generated from C57BL/6 mice using an intratracheally injected Adeno-virus that contains Cas9 and guide RNAs targeting the Trim24 and Ret genes. This induces a gene rearrangement producing the Trim24-Ret fusion gene and the development of lung tumors. A cell line, TR.1 was derived from a resulting lung tumor. In an effort to understand how TR.1 cells respond to selpercatinib and pralsetinib, we treated TR.1 cells in vitro for 1-5 days with either 100nM selpercatinib or DMSO-control. In addition, TR.1 cells were made resistant to selpercatinib and pralsetinib through established dose-escalation in vitro until cultures that were resistant to ~500 nM TKI were established. TR.1 cells cultured in 0.1% DMSO over the same timeframe were used as controls. At each time point or condition, RNA was isolated and submitted to bulk RNA-seq. These data will allow a deeper understanding of mechanisms mediating acquired resistance in RET fusion-positive patients