CCDC6-RET fusion

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.

In this case report, we describe a case of sequential acquired CCDC6 -RET fusion and BRAF V600E mutation observed in a patient with EGFR-mutated NSCLC treated with osimertinib and with combined selpercatinib and osimertinib. When a novel BRAF V600E mutation was detected at progression, the molecular tumor board suggested the administration of triple therapy, adding trametinib (anti-MEK). Nevertheless, treatment was discontinued for toxicity, highlighting the challenges of using multiple drug combinations to address complex resistance.

She was then treated with a combination of selpercatinib and trametinib, which led to a likely partial response, despite the combination demonstrating side effects. This case report details the first known instance of NSCLC with a RET fusion developing resistance by means of a BRAF fusion, treated with combined RET and MEK inhibition.

Although RET-positive tumors have been treated with multikinase inhibitors such as vandetanib or RET-selective inhibitors, ultimately resistance to them develops...Increased mitochondria were also observed in post-TKI biopsy specimens in 13/20 cases of NSCLC, suggesting a potential strategy targeting mitochondria to treat resistant tumors. Our data propose new promising therapeutic options to combat resistance to RET inhibitors in NSCLC.

The patient was initiated on selpercatinib, which was held after 3 weeks due to thrombocytopenia and hypertension. Pralsetinib was held during adjuvant chemoradiation for the GBM, and again for 4 weeks due to pneumonitis that resolved with steroids, and pralsetinib was restarted at a reduced dose. The patient has since demonstrated a stable reduction of the mediastinal mass for >15 months with RET inhibition therapy, despite several treatment interruptions.

We previously showed that the multi-kinase inhibitors vandetanib and cabozantinib increase the mitochondrial membrane potential (Δψm) in RET-mutated thyroid tumor cells and that this effect can be exploited to increase mitochondrial enrichment of Δψm-sensitive agents in the tumor cells...The quality of life of one patient significantly improved over a year until the tumor relapsed. This combination of selpercatinib with MitoQ may have therapeutic potential for patients with RET-mutated tumors and intolerant to regular selpercatinib doses.

Of four patients with PD-L1 overexpression (>50%) one received pembrolizumab and the other three patients received pemetrexed, carboplatin, and pembrolizumab or camrelizumab. Fifteen patients received selective RET inhibitors (pralsetinib and selpercatinib), resulting in an ORR of 53.3% (8/15) and median PFS of 10.0 months (95% CI 5.2-14.9). ICIs for PD-L overexpression and treatment naive patients offer comparable benefits for RET fusion-positive NSCLC, warranting further investigation.

NGS after EGFR-TKI resistance may detect targetable drivers besides T790M. To do either liquid or tissue NGS only could miss patients with T790M. To do tissue and liquid NGS in parallel after EGFR-TKI resistance may find more patients with targetable cancers.