CCDC6-RET fusion

The patient died five months after diagnosis. This case illustrates the diagnostic and therapeutic challenges posed by rare, highly aggressive CNS neoplasms that do not map to a WHO-defined entity on available testing and highlights the potential clinical relevance of identifying actionable RET fusions in high-grade neuroepithelial tumors.

Pralsetinib was added to osimertinib, resulting in a response lasting 4 months...After one month with alectinib only, osimertinib was added due to the progression, resulting in another response of more than two months. Upon progression with quadruple alterations (EGFR 19del, EGFR C797S, MET amplification, and RET fusions), cabozantinib-gefitinib combination was initiated, leading to rapid deterioration...At the same time, comprehensive genomic testing remains essential for therapeutic decision-making, with ctDNA analysis complementing tissue-based approaches. Notably, the FGFR3-TACC3 fusion may represent a novel resistance mechanism contributing to the limited efficacy of EGFR-TKI.

Upon nucleotide binding the catalytic domains swing apart and fast activation loop phosphorylation could be driven by a mechanism in cis. Our work uncovers the molecular and structural determinants that control the mechanism of CCDC6-RET autoactivation.

A combined strategy with continued osimertinib and addition of the selective RET inhibitor selpercatinib was pursued based on biological rationale; however, the short duration of combined treatment precluded a meaningful assessment of clinical benefit. This case highlights the importance of molecular reassessment at progression to identify rare but actionable resistance mechanisms that may significantly influence therapeutic strategy in EGFR-mutant NSCLC.

Although selective RET inhibitors such as selpercatinib and pralsetinib have been clinically approved, the emergence of resistance mutations limits their durable efficacy, underscoring the need for novel therapeutic modalities. We report the design and synthesis of the first RET-targeting HyTTD, compound B2, which achieves 91.4% degradation of CCDC6-RET fusion protein in TPC-1 cells at 10 μM within 48 h. These results not only validate hydrophobic tag tethering as a feasible strategy for RET degradation but also propose a new therapeutic direction for RET-driven cancers.

A 67-year-old woman with EGFR exon 19-deleted adenocarcinoma received afatinib followed by long-term osimertinib. CSF liquid biopsy provided actionable, compartment-specific genotyping that outperformed cytology and guided effective retreatment. Incorporating CSF ctDNA into routine evaluation may improve therapeutic alignment across sanctuary sites; when feasible, maintaining EGFR blockade should be considered when CNS involvement is suspected in EGFR-mutated NSCLC in routine practice.

We investigated the growth-inhibitory effects of everolimus, an mTOR inhibitor, and found that TPC-1, TPC-1/SELR, and CUTC48 cells were highly sensitive to the drug. Our results suggest the involvement of AKT-mTOR pathway activation in selpercatinib resistance in thyroid cancer and that inhibition of the AKT-mTOR pathway may have therapeutic potential to overcome selpercatinib resistance.

Molecular testing substantially improves diagnostic accuracy when integrated with cytology, facilitating the diagnosis of cytologically indeterminate nodules and offering prognostic insights for TC patients.

The present case study reported on a patient with advanced PTC who developed ORN during lenvatinib treatment; extensive surgical treatment with submandibular dissection for ORN provided a favorable outcome...CGP identified a CCDC6-RET fusion, prompting selpercatinib treatment, which achieved a partial response...In addition, submandibular dissection is warranted in selected patients, particularly when thyroid cancer exhibits an aggressive phenotype with occult metastases. Furthermore, this report highlights the importance of integrating personalized medicine in the management of advanced cancer cases and emphasizes the availability of genomic profiling to guide treatment decisions.

RET solvent-front G810C/R/S mutations confer resistance to the currently approved RET protein tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib. Among three compounds (HSN748, HSND19, and HSN608) evaluated for B/KR(G810C) brain tumors, HSN748 exhibited significant intracranial tumor inhibition. PK analysis indicated that HSN748 has a brain/plasma partition coefficient (K p) of 0.4, demonstrating its capability to penetrate the central nervous system (CNS).

Molecular testing is not necessary for histologic subtyping but can aid in the differential diagnosis of IC.