In 1985, Takahashi and colleagues cloned a novel oncogene from human T-cell lymphoma, naming it “rearranged during transfection” (RET), which is now known by its gene symbol RET. The oncogene was generated by recombining 2 unlinked DNA fragments during the transfection procedure.

Toward the end of that decade, researchers were able to show that RET encodes a receptor tyrosine kinase involved in fetal development of the hematopoietic, GI, nervous, and GU systems. Over the next several years, RET alterations via gene fusions and point mutations were identified as oncogenic drivers in papillary thyroid, medullary thyroid, NSCLC, colorectal, and breast cancers, among others.

Initial targeted therapy for RET-altered cancer consisted of multikinase inhibitors with RET inhibitory activity. At that time, treatment was limited by modest effectiveness and off-target adverse events, lending urgency to the development of RET-specific therapy.

Much work has been done since the 1980s and 1990s. Presently, certain selective RET inhibitors are approved for RET fusion–positive NSCLC and thyroid cancer as well as RET-mutated medullary thyroid cancer, and, in one case, can be tumor agnostic.

Have you used selective RET inhibitors in patients with RET-altered cancers? What are the benefits and challenges of these therapies?