Novel RET Fusion RET-SEPTIN9 Predicts Response to Selective RET Inhibition With Selpercatinib in Malignant Pheochromocytoma

A RET::GRB2 fusion in pheochromocytoma defies the classic paradigm of RET oncogenic fusions

“…The recently reported RET::SEPTIN9 fusion in a metastatic pheochromocytoma 10 is relevant to our findings. This fusion had a similar configuration to RET::GRB2 by positioning RET as the 5′ partner, and the patient showed marked clinical response to selpercatinib, in favor of the fusion playing a driver role and being therapeutically sensitive to RET inhibition, similar to our in vitro data of RET::GRB2 .…”

“… 1 Y1062 is retained in typical RET fusions, where RET is the 3′ prime partner, 1 , 3 and also in the RET::SEPTIN9 fusion described in a pheochromocytoma. 10 In contrast, this site is abolished by the RET::GRB2 fusion, which contains only the first 1,013 amino acids of RET. Accordingly, we were unable to detect phosphorylated Y1062 both at baseline and after GDNF exposure, while this phosphorylation is expectably detectable in cells expressing wild-type (WT) RET9 and RET 51 ( Figure 2 E).…”

“…However, the true frequency of RET 5′ recombinations in cancer is unknown, as current fusion diagnostic platforms routinely focus on hot-spot RET intronic breakpoints involving introns 11 and 12, 24 which would not have detected RET::GRB2 or RET::SEPTIN9 events. 10 Notably, neither SEPTIN9 nor GRB2 possess coiled-coil domains, a frequent feature of the more common fusion partners of RET in lung and thyroid cancers. 3 It remains to be determined whether this RET fusion configuration is exclusive to pheochromocytomas or if it can also be detected in other neural-crest-derived tumors or, even more broadly, in other cancers.…”

“…Notably, the patient displayed a marked clinical response to selpercatinib. 10 In this report, we describe RET::GRB2, a distinct fusion in a sporadic pheochromocytoma, in which RET functions as the upstream component of the hybrid protein, in a similar configuration to the RET::SEPTIN9 fusion, although with a distinct RET breakpoint. Unlike other RET fusions, the C-terminal partner of this fusion, GRB2, is a known RET adaptor protein and signaling mediator.…”

Pediatric Metastatic Pheochromocytoma and Paraganglioma: Clinical Presentation and Diagnosis, Genetics, and Therapeutic Approaches

“…Mweempwa et al demonstrated efficacy of a selective RET inhibitor (selpercatinib) in metastatic PCC due to an activating gene fusion of RET-SEPTIN9 in an adult with recurrent PCC with biopsy-confirmed metastatic disease to the lungs and liver with negative urinary metanephrines but highly elevated chromogranin A (33,710 µg/L). After 12 weeks of therapy with selpercatinib, chromogranin A had decreased to 598 µg/L, and pulmonary and hepatic tumors demonstrated reduction in size on CT (46% in the sum of diameters of lesions), raising the possibility that this targeted therapy may also be useful for pediatric patients with activating RET mutations; however additional studies are needed (83). Similarly, targeted therapy directed by the genetic background may also inform the approach to patients with NF-1.…”