From MEK inhibition to rational combination strategies for NF1-associated plexiform neurofibromas

Plexiform neurofibromas (PNs) are among the most clinically burdensome tumor manifestations of neurofibromatosis type 1 (NF1) and can cause pain, disfigurement, neurological deficits, and compression of vital structures. Their diffuse growth along nerves and blood vessels often limits complete surgical resection. Biallelic NF1 loss results in persistent activation of RAS–RAF–MEK–ERK signaling and provides a strong biological rationale for MEK inhibition. Selumetinib and mirdametinib have received regulatory approval in defined patient populations, while trametinib, luvometinib, and other MEK inhibitors have also demonstrated clinical activity. Nevertheless, responses remain predominantly partial. Some patients show primary nonresponse, limited tumor shrinkage, or treatment-limiting toxicity, and tumor regrowth may occur after dose reduction or treatment discontinuation. This review first summarizes molecular mechanisms and monotherapy evidence, then evaluates rational combinations and their clinical translation. These strategies include vertical inhibition of RAS–MAPK signaling, blockade of parallel survival pathways, targeting of residual tumor-cell states, and modulation of the tumor microenvironment. Combined MEK and SOS1 inhibition has relatively strong PN-specific in vivo support. KRAS–MEK inhibition has emerging mouse-model support, while selumetinib plus cabozantinib is undergoing clinical dose exploration. Strategies targeting CDKs or YAP/TEAD warrant further translational evaluation. In contrast, negative or borderline findings involving SHP2, mTOR, and several microenvironment-directed approaches demonstrate that biological plausibility does not necessarily translate into therapeutic benefit. Because NF1-associated PNs are predominantly benign tumors requiring long-term management, rational combination therapy should not simply increase treatment intensity. Instead, it should address a defined limitation of monotherapy and demonstrate a favorable net clinical benefit over an active single agent. Future treatment may therefore evolve toward mechanism-guided approaches incorporating reduced-dose combinations, sequential or intermittent therapy, rechallenge, and surgery after pharmacological tumor reduction. Tumor volume, pain, function, long-term safety, resectability, and disease control after treatment withdrawal should collectively inform therapeutic value.