RET aberrant cancers and RET inhibitor therapies: Current state-of-the-art and future perspectives

Alfredo Addeo; Ernesto Miranda-Morales; Petra den Hollander; Alex Friedlaender; Herman O Sintim; Jie Wu; Sendurai A Mani; Vivek Subbiah

doi:10.1016/j.pharmthera.2023.108344

RET aberrant cancers and RET inhibitor therapies: Current state-of-the-art and future perspectives

Pharmacol Ther. 2023 Feb:242:108344. doi: 10.1016/j.pharmthera.2023.108344. Epub 2023 Jan 9.

Authors

Alfredo Addeo¹, Ernesto Miranda-Morales², Petra den Hollander³, Alex Friedlaender¹, Herman O Sintim⁴, Jie Wu⁵, Sendurai A Mani³, Vivek Subbiah⁶

Affiliations

¹ Oncology Department, University Hospital Geneva (HUG), Geneva, Switzerland.
² Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02903, USA; Legorreta Cancer Center, Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.
⁴ Purdue Institute for Cancer Research, Institute for Drug Discovery and Department of Chemistry, West Lafayette, IN, USA.
⁵ Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁶ Department of Investigational Cancer Therapeutics(,) Division of Cancer Medicine, Unit 455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA; Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; MD Anderson Cancer Network, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: vsubbiah@mdanderson.org.

Abstract

Precision oncology informed by genomic information has evolved in leaps and bounds over the last decade. Although non-small cell lung cancer (NSCLC) has moved to center-stage as the poster child of precision oncology, multiple targetable genomic alterations have been identified in various cancer types. RET alterations occur in roughly 2% of all human cancers. The role of RET as oncogenic driver was initially identified in 1985 after the discovery that transfection with human lymphoma DNA transforms NIH-3T3 fibroblasts. Germline RET mutations are causative of multiple endocrine neoplasia type 2 syndrome, and RET fusions are found in 10-20% of papillary thyroid cases and are detected in most patients with advanced sporadic medullary thyroid cancer. RET fusions are oncogenic drivers in 2% of Non-small cell lung cancer. Rapid translation and regulatory approval of selective RET inhibitors, selpercatinib and pralsetinib, have opened up the field of RET precision oncology. This review provides an update on RET precision oncology from bench to bedside and back. We explore the impact of selective RET inhibitor in patients with advanced NSCLC, thyroid cancer, and other cancers in a tissue-agnostic fashion, resistance mechanisms, and future directions.

Keywords: Clinical trials; Non-small cell lung cancer; RET; RET fusions; Thyroid cancer; Tissue-agnostic.

Publication types

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

MeSH terms

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding