RET mutation

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.

This case underscores the value of liquid biopsy detected mutations in guiding targeted therapy. Clinical, biochemical, and radiological findings support the potential use of selective RET tyrosine kinase inhibitors for this rare mutation. Serum calcitonin serves as a reliable quantitative biomarker of therapeutic efficacy.

The observation is hypothesis-generating rather than proof of sensitivity. This case provides a reference for precision treatment strategies after resistance to RET inhibitors.

The patient was treated with selpercatinib, resulting in radiographic response and clearance of circulating RET-mutant DNA. She remains progression-free 10 months into therapy and the infant continues normal development. This is the first reported case of RET p.M918T-mutated neuroendocrine lung cancer with placental metastases diagnosed during pregnancy, highlighting the importance of molecular profiling and multidisciplinary care.

Pralsetinib and selpercatinib are novel, highly selective RET tyrosine kinase inhibitors (RET-TKIs). Given the low prevalence of RET gene alterations (＜5%), which are regarded as rare genetic mutations, clinical experience in the use pf RET-TKIs and and patient management remains limited. Base on the current status of adverse event management of RET-TKIs in China, and integrating the latest international evidence and clinical experience, the Chinese Medical Doctor Association Tumor Multidisciplinary Diagnosis and Treatment Professional Committee and the Shenzhen Medical Doctor Association Tumor Multidisciplinary Diagnosis and Treatment Professional Committee organized discussion among experts from medical oncology, respiratory medicine, radiation oncology, thoracic surgery, and other related disciplines to formulate this expert consensus on the management of adverse events of RET-TKIs.

P2, N=78, Recruiting, Shanghai Junshi Bioscience Co., Ltd. | N=42 --> 78 | Trial completion date: Apr 2027 --> Apr 2028 | Trial primary completion date: Sep 2025 --> Sep 2026

We further discuss emerging therapeutic strategies targeting glucose metabolism and highlight challenges including isoform-specific regulation and biomarker-driven patient stratification. This review provides a conceptual framework for translating metabolic insights into improved diagnosis and therapy for TC.

Notably, within the RAS-mutant subgroup, the presence of co-occurring oncogenic alterations was associated with more advanced T status (T3-T4, p = 0.0181) at diagnosis and lower biochemical cure rates (p = 0.02) at the follow-up compared with tumors harboring isolated RAS mutations, supporting the clinical relevance of extended genomic profiling in RAS-mutant sMTC. Overall, these findings highlight additional oncogenic alterations potentially involved in tumor progression and suggest that extended targeted profiling may provide clinically relevant information on molecular heterogeneity in sMTC, particularly within RAS-mutant tumors.

Several multikinase blockers targeting RET have been approved by the FDA for the treatment of cancer: (i) vandetanib for medullary thyroid carcinoma and (ii) cabozantinib, lenvatinib, and sorafenib for differentiated thyroid cancer. Pralsetinib is a specific RET blocker that is FDA-approved for the treatment of medullary thyroid cancer, RET-fusion positive thyroid cancer and NSCLC. Selpercatinib is FDA-approved for the management of RET-mutant medullary thyroid cancer, RET-fusion-positive thyroid cancer, and other RET-fusion-positive solid tumors...Currently, the number of new cases of thyroid cancer bearing RET mutations or RET-fusion proteins is about 13,000 per year and the number of cases of RET-driven NSCLC range from about 2000-4000 per year in the United States. Inactivating RET mutations result in Hirschsprung disease, a congenital disorder leading to aganglionosis of the gastrointestinal tract.

We present a case of a 66-year-old female with de novo metastatic NSCLC harboring an EGFR mutation, RET rearrangement, and ERBB2 amplification, who experienced transformation to SCLC while on osimertinib. Subsequently, she exhibited primary refractory disease to both first-line platinum doublet with immunotherapy and second-line lurbinectedin...The patient had minimal side effects and obtained a partial response with a progression-free survival (PFS) of 13.1 months, better than historically poor prognosis seen in transformed SCLC. This case underscores the potential role of human epidermal growth factor receptor 2 (HER-2) directed therapies, such as T-DXd, in transformed SCLC.