RET (Ret Proto-Oncogene)

Resistance to RET inhibitors can be acquired through RET copy-number gain and secondary mutations as well as NF1 loss-mediated MAPK pathway activation. This mechanism of resistance can be overcome with dual inhibition of RET and downstream RAS/MAPK signaling, demonstrating clinical potential in RET-mutant MTC.

Among cases with follow-up data (n=35), all 17 tumors with disease progression were DLL3 positive (13 RET-mutated tumors, 1 RAS-mutated tumor, and 3 RET/RAS wild-type tumors), including 5 with moderate expression and 12 with high expression. Most MTCs express DLL3; moreover, DLL3 expression is associated with lymph node metastases at diagnosis and disease progression, indicating that DLL3 may be an effective therapeutic target in MTC.

The present investigation suggests that tumor progression in MTC before clinical detection is a function of the time passed since tumor onset, whereas tumor onset is defined by the transformatory strength of the RET mutation. This notion, debunking the myth of immanent tumor 'aggressiveness' or "risk" imparted by RET mutations in favor of the concept of genetically encoded tumor onset, emphasizes the need for early diagnosis and intervention, ideally while tumors are still confined to the thyroid.

P2, N=32, Not yet recruiting, University of Washington | Initiation date: Jun 2026 --> Sep 2026

This case demonstrates that for selected patients with advanced lung adenocarcinoma harboring a CCDC6-RET fusion and oligometastatic disease, initial systemic therapy with selpercatinib followed by local consolidative surgery is a feasible multimodal strategy. This is not a routine recommendation for stage IV lung cancer but requires individualized decision-making after multidisciplinary discussion in specific oligometastatic cases.

Selpercatinib, a RET inhibitor, is covered by insurance for all solid tumors that are positive for the RET fusion gene...In other solid tumors, positivity is less than 0.5%. However, if positive, treatment is expected to be effective, so it is desirable to actively perform cancer gene panel testing.

The patient did not respond to gemcitabine and cisplatin-based systemic chemotherapy. Selpercatinib, a selective inhibitor of receptor tyrosine kinase RET, blocks RET kinase activity by binding to its adenosine triphosphate-binding site, thus preventing the kinase from phosphorylating substrates and halting oncogenic signaling. The patient was treated with selpercatinib, which produced a durable response lasting over 15 months in this chemotherapy-refractory patient, highlighting the efficacy of selpercatinib in HOOK3-RET fusion-positive pancreatic cancer.

Continuous genomic monitoring is essential for identifying resistance mechanisms and guiding precision therapy. Future studies should explore the impact of different fusion partners on tumor behavior and therapeutic response.

P1, N=16, Recruiting, Memorial Sloan Kettering Cancer Center

Results from LIBRETTO-432 demonstrate that adjuvant selpercatinib yields a substantial improvement in event-free survival for patients with early-stage RET fusion-positive non-small cell lung cancer. Experts say the findings establish selpercatinib as a new standard of care for this rare disease, although questions remain over identifying patients and access to screening.

Among patients with stage II or IIIA RET fusion-positive NSCLC, event-free survival was significantly longer with adjuvant selpercatinib than with placebo. (Funded by Lilly; LIBRETTO-432 ClinicalTrials.gov number, NCT04819100.).