Precision therapy for RET-altered cancers with RET inhibitors

Kyaw Z Thein; Vamsidhar Velcheti; Blaine H M Mooers; Jie Wu; Vivek Subbiah

doi:10.1016/j.trecan.2021.07.003

Precision therapy for RET-altered cancers with RET inhibitors

Trends Cancer. 2021 Dec;7(12):1074-1088. doi: 10.1016/j.trecan.2021.07.003. Epub 2021 Aug 12.

Authors

Kyaw Z Thein¹, Vamsidhar Velcheti², Blaine H M Mooers³, Jie Wu⁴, Vivek Subbiah⁵

Affiliations

¹ Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Division of Hematology and Medical Oncology, Oregon Health and Science University/Knight Cancer Institute, Portland, OR 97239, USA.
² Department of Medicine, NYU Langone- Laura and Isaac Perlmutter Cancer Center, New York, NY 10016, USA.
³ Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Laboratory of Biomolecular Structure and Function, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
⁴ Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
⁵ Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; MD Anderson Cancer Network, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: [email protected].

Abstract

Rearranged during transfection (RET) is involved in the physiological development of some organ systems. Activating RET alterations via either gene fusions or point mutations are potent oncogenic drivers in non-small cell lung cancer, thyroid cancer, and in multiple diverse cancers. RET-altered cancers were initially treated with multikinase inhibitors (MKIs). The efficacy of MKIs was modest at the expense of notable toxicities from their off-target activity. Recently, highly potent and RET-specific inhibitors selpercatinib and pralsetinib were successfully translated to the clinic and FDA approved. We summarize the current state-of-the-art therapeutics with preclinical and clinical insights of these novel RET inhibitors, acquired resistance mechanisms, and future outlooks.

Keywords: BLU-667 (pralsetinib); LOXO-292 (selpercatinib); RET-altered cancers; lung cancer; multikinase inhibitors; thyroid cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Carcinoma, Non-Small-Cell Lung* / drug therapy
Humans
Lung Neoplasms* / drug therapy
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins c-ret / genetics
Proto-Oncogenes

Substances

Protein Kinase Inhibitors
Proto-Oncogene Proteins c-ret
RET protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding