The L730V/I RET roof mutations display different activities toward pralsetinib and selpercatinib

Tao Shen; Xueqing Hu; Xuan Liu; Vivek Subbiah; Blaine H M Mooers; Jie Wu

doi:10.1038/s41698-021-00188-x

The L730V/I RET roof mutations display different activities toward pralsetinib and selpercatinib

NPJ Precis Oncol. 2021 Jun 7;5(1):48. doi: 10.1038/s41698-021-00188-x.

Authors

Tao Shen^#^{1

2}, Xueqing Hu^#^{1

2}, Xuan Liu^#^{1

2}, Vivek Subbiah³, Blaine H M Mooers^{1

4

5}, Jie Wu^{6

7}

Affiliations

¹ Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
² Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
³ Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁵ Laboratory of Biomolecular Structure and Function, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁶ Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. jie-wu@ouhsc.edu.
⁷ Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. jie-wu@ouhsc.edu.

^# Contributed equally.

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.

Abstract

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