Koselugo (selumetinib)

Due to the lesion's inoperable location and risk of vascular and biliary compression, targeted therapy with the MEK inhibitor selumetinib was indicated. The patient is currently awaiting provision of the medication. This case underscores the importance of careful monitoring and early initiation of targeted therapy in NF1 patients with extensive plexiform neurofibromas, particularly those caused by large NF1 gene deletions, which result in complete loss of neurofibromin and extensive infiltrative benign tumor growth.

P2, N=57, Active, not recruiting, University Health Network, Toronto | Trial completion date: Sep 2026 --> Sep 2027 | Trial primary completion date: May 2026 --> May 2027

Furthermore, we use the 3D NC spheroid models to discover drugs targeting MPNSTs through high-throughput screening of epigenetic compounds. Poly(ADP-ribose) polymerase inhibitors (PARPi) exhibit selective efficacy in PRC2-deficient NC spheroids and Olaparib-Selumetinib combination is well tolerated and significantly suppresses tumor growth in a human MPNST PDX mouse model.

While rigorous clinical trial data is still emerging, these preliminary cases suggest selumetinib may be a safe and effective therapeutic option for NF1-related OPGs, offering significant tumour control with a favourable toxicity profile compared to chemotherapy. Beyond stabilization, its potential to restore visual function represents a major advance, supporting the potential role of MEK inhibition as a first- and second-line treatment strategy.

In this prospective case series selumetinib appeared to be a useful drug for the treatment of PNs.

Moreover, MEK inhibitor (AZD-6244) intervention studies confirmed that CPT inhibits EMT by targeting the MEK pathway...Our results demonstrated that CPT modulates breast cancer migration and invasion via the MEK/ERK/EMT axis by directly targeting MEK1. Our study provides evidence suggesting that CPT may serve as a potential agent for suppressing breast cancer metastasis.

The cytotoxic effects of three MAPK pathway inhibitors (selumetinib, vemurafenib, dabrafenib) were assessed in ATC cell lines and xenograft models via viability assays and 18F-FDG PET/CT. Furthermore, MAPK pathway inhibitors increased radioiodine uptake in ATC cells. The MAPK pathway inhibitors enhance NIS function through two mechanisms: upregulation of NIS expression and increased ARF4-mediated NIS membrane transport.

P1/2, N=31, Not yet recruiting, National Cancer Institute (NCI)

P1, N=58, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2025 --> Mar 2027

While the mitogen-activated protein kinase kinase (MEK) inhibitors, selumetinib and mirdametinib, can reduce tumor volume, surgical resection remains the primary treatment for immediate debulking and symptom relief. These results provide the first evidence that ECM stiffening, including that plausibly associated with postsurgical remodeling, may contribute to pNF1 growth and reduced sensitivity to selumetinib in this 3D pNF1 culture model. Our findings highlight mechanobiology as a key regulator of tumor behavior and support further investigation of ECM-targeted strategies to improve outcomes in neurofibromatosis type 1 (NF1).

Osimertinib plus selumetinib demonstrated minimal response in patients with EGFR-mutated advanced NSCLC with BRAF alterations following disease progression on first-line osimertinib. The safety profile of the combination was consistent with the known profiles of the two individual drugs; no new safety signals were identified. Overall, the risk-benefit profile suggests further evaluation of this combination is not warranted.

P1, N=140, Completed, AstraZeneca | Active, not recruiting --> Completed