TEAD inhibitors re-sensitize drug-resistant NF1 MPNST cells to MEK inhibitors.

Neurofibromatosis type 1 (NF1) patients develop non-malignant neurofibromas that can progress to Malignant Peripheral Nerve Sheath Tumors (MPNSTs). NF1 neurofibromas are treated with MEK inhibitors, such as mirdametinib and selumetinib, because they are driven by activation of the Ras/Raf/MEK/ERK signaling pathway. We developed two MEK-resistant MPNST cell lines by passaging cells in selumetinib for approximately three months. The cells were resistant to 15 other MEK inhibitors in a high-throughput screen but were re-sensitized by co-treatment with a TEAD inhibitor. These results suggest that TEAD inhibitors synergize with MEK inhibitors to overcome resistance and enhance therapeutic efficacy in MPNSTs.