RET-Altered Cancers—A Tumor-Agnostic Review of Biology, Diagnosis and Targeted Therapy Activity

SIMPLE SUMMARY: Changes in the RET gene (like mutations or fusions) are often found in lung and thyroid cancers but are also found in other cancer types. New drugs called “selective RET inhibitors”, like selpercatinib and pralsetinib, are effective in treating tumors with RET gene changes. These drugs have been tested in “basket trials” that treat patients based on gene changes in their cancer instead of cancer type. In this review, we discuss how RET gene changes cause cancer, which cancers have these changes, what tests to use, and how well targeted therapies work. ABSTRACT: RET alterations, such as fusions or mutations, drive the growth of multiple tumor types. These alterations are found in canonical (lung and thyroid) and non-canonical (e.g., gastrointestinal, breast, gynecological, genitourinary, histiocytic) cancers. RET alterations are best identified via comprehensive next-generation sequencing, preferably with DNA and RNA interrogation for fusions. Targeted therapies for RET-dependent cancers have evolved from older multikinase inhibitors to selective inhibitors of RET such as selpercatinib and pralsetinib. Prospective basket trials and retrospective reports have demonstrated the activity of these drugs in a wide variety of RET-altered cancers, notably those with RET fusions. This paved the way for the first tumor-agnostic selective RET inhibitor US FDA approval in 2022. Acquired resistance to RET kinase inhibitors can take the form of acquired resistance mutations (e.g., RET G810X) or bypass alterations.