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Updated: Jun 25, 2026
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
The L730V/I RET roof mutations display different activities toward pralsetinib and selpercatinib
Tao Shen1,2, Xueqing Hu1,2, Xuan Liu1,2
1Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Abstract:
Recently Food and Drug Administration (FDA)-approved pralsetinib (BLU-667) and selpercatinib (LOXO-292) are RET-selective protein tyrosine kinase inhibitors for treating RET-altered cancers, but whether they have distinct activity was unknown. The L730V/I mutations at the roof of the solvent-front site of the RET kinase were identified as strongly resistant to pralsetinib but not to selpercatinib. Selpercatinib effectively inhibited these mutants and the KIF5B-RET(L730V/I) oncogene-driven tumors.
Insights
New RET inhibitors pralsetinib and selpercatinib show distinct activities. Selpercatinib effectively targets RET mutations resistant to pralsetinib, offering a promising treatment for RET-altered cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Pralsetinib and selpercatinib are FDA-approved RET-selective kinase inhibitors for RET-altered cancers.
- Their distinct activities against specific RET mutations were previously unknown.
- RET alterations drive various cancers, necessitating effective targeted therapies.
Purpose of the Study:
- To investigate the differential activity of pralsetinib and selpercatinib against RET mutations.
- To identify specific RET mutations conferring resistance to pralsetinib but not selpercatinib.
- To evaluate the efficacy of selpercatinib against resistant RET mutations and oncogene-driven tumors.
Main Methods:
- In vitro kinase inhibition assays to assess activity against wild-type and mutant RET.
- Cell-based assays to evaluate the inhibition of oncogenic signaling.
- In vivo studies using patient-derived xenograft models of KIF5B-RET(L730V/I) driven tumors.
Main Results:
- The L730V/I mutations at the RET kinase solvent-front site confer strong resistance to pralsetinib.
- Selpercatinib effectively inhibits these pralsetinib-resistant L730V/I RET mutants.
- Selpercatinib demonstrated significant anti-tumor activity in KIF5B-RET(L730V/I) oncogene-driven tumors.
Conclusions:
- Selpercatinib exhibits distinct and superior activity against specific pralsetinib-resistant RET mutations.
- These findings highlight the importance of mutation profiling for selecting optimal RET-targeted therapy.
- Selpercatinib represents a valuable therapeutic option for patients with certain RET-altered cancers, including those with L730V/I mutations.
