Progress and challenges in RET-targeted cancer therapy

Abstract

The rearranged during transfection (RET) is a receptor protein tyrosine kinase. Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer (NSCLC) and in thyroid cancer, but also increasingly in various types of cancers at low rates. In the last few years, two potent and selective RET protein tyrosine kinase inhibitors (TKIs), pralsetinib (BLU-667) and selpercatinib (LOXO-292, LY3527723) were developed and received regulatory approval. Although pralsetinib and selpercatinib gave high overall response rates (ORRs), < 10% of patients achieved a complete response (CR). The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations, acquired alternative oncogenes, or MET amplification. RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib. Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials. However, it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs. Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors.

Keywords

pralsetinib / selpercatinib / RET-alteration / lung cancer / thyroid cancer / tumor-agnostic therapy / drug resistance

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Acknowledgements

Cancer research in Jie Wu’s laboratory was supported by NIH grants R01CA242845, R01CA273168, a PHF SEED grant; Oklahoma Center for the Advancement of Science and Technology (OCAST) grant HR19-026. Additional support was provided by the Oklahoma Tobacco Settlement Endowment Trust, and the Peggy and Charles Stephenson Endowment, and NIH grants P30CA225520 and P20GM103639 to the institution.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-0985-y and is accessible for authorized users.

Compliance with ethics guidelines

Xueqing Hu, Ujjwol Khatri, Tao Shen, and Jie Wu declare that they have no conflicts of interest. This manuscript is a review article and does not involve a research protocol that requires the approval of relevant institutional review board or ethics committee.

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