Koselugo (selumetinib)

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

To overcome resistance to MEK inhibitors such as selumetinib in neurofibroma, we developed a metabolism-targeted nanotherapeutic based on a pH-responsive silver nanoparticle platform (AgNP-PEG-TC) for delivering Triacsin C (TC), an inhibitor of long-chain acyl-CoA synthetases, to disrupt tumor-associated lipid metabolism...These findings establish a metabolism-nanotechnology synergy in which AgNP-PEG-TC-mediated ACSL4 inhibition and lipid metabolic reprogramming resensitize MEK inhibitor-resistant neurofibromas to therapy. The platform functions as both a targeted drug carrier and a modulator of tumor lipid homeostasis, offering a promising combinatorial strategy.

MEK inhibitor therapy is associated with significant improvements in patient-reported pain outcomes in NF1-associated PN, including reductions in pain intensity and interference, as well as a high proportion of patients achieving clinically meaningful improvement. While the average reduction in pain intensity did not reach the threshold for clinically meaningful change at the population level, responder analyses demonstrate substantial benefit in a significant subset of patients. These findings support the role of MEK inhibitors as a disease-modifying therapy with meaningful symptomatic benefit.