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.
Kyaw Z Thein  1 ,  Vamsidhar Velcheti  2 ,  Blaine H M Mooers  3 ,  Jie Wu  4 ,  Vivek Subbiah  5
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].
PMID: 34391699 DOI: 10.1016/j.trecan.2021.07.003
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.
Products