Trametinib and Fimepinostat Induce Malignant Peripheral Nerve Sheath Tumor Cell Death In Vitro

TL;DR

Trametinib and fimepinostat show promise in killing MPNST cells in lab tests, potentially offering better treatment options for NF1 patients.

Contribution

The study demonstrates that trametinib and fimepinostat are more effective than current drugs in inhibiting MPNST cell growth in vitro.

Findings

Trametinib induced cell death in 7 out of 9 MPNST cell lines with a geometric mean GI50 of 17 nM.

Fimepinostat caused cell death in all 9 MPNST cell lines with a geometric mean GI50 of 17 pM.

Trametinib outperformed selumetinib and mirdametinib in blocking ERK1/2 phosphorylation for 24 hours.

Abstract

Malignant peripheral nerve sheath tumors are deadly tumors that develop in patients with Neurofibromatosis Type 1 (NF1). There are currently no effective treatments for these tumors, and NF1 patients with MPNSTs face bleak odds of survival including death in adolescence and early adulthood. New drugs currently entering clinical trials for MPNSTs include inhibitors of MEK and HDAC enzymes. The authors present evidence that the MEK inhibitor trametinib and dual HDAC/PI3K inhibitor fimepinostat could be more efficacious in MPNST patients than the drugs currently under clinical investigation. This conclusion is supported by timelapse imaging data collected from nine unique patient-derived MPNST cell lines. The results presented here confirm previous preclinical studies and a case report and inform future MPNST clinical trials.

Background/Objectives: Neurofibromatosis Type 1 (NF1) is a genetic syndrome caused by pathogenic NF1 variants encoding neurofibromin, a Ras GTPase activating protein. Individuals with NF1 develop peripheral nerve sheath tumors called neurofibromas. Approximately 50% of NF1 patients develop plexiform neurofibromas (pNFs) which have up to 13% lifetime risk of transformation into malignant peripheral nerve sheath tumors (MPNSTs). Current therapeutic strategies emphasize surgical resection with wide margins, radiation, and traditional chemotherapy for unresectable MPNSTs. However, NF1 patients diagnosed with MPNSTs have 5-year survival rates as low as 16%. The two recently FDA-approved drugs for pNFs, the MEK inhibitors selumetinib and mirdametinib, are not used to prevent or treat MPNSTs. Methods: The MEK inhibitor trametinib and the dual HDAC/PI3K inhibitor fimepinostat were assessed for growth inhibitory effects in nine unique patient-derived MPNST cell lines, as both drugs have preclinical efficacy in other Schwann cell-derived tumors. Results: Trametinib, which is approved for malignant melanomas, promoted cell death in 7/9 MPNST cell lines with a geometric mean GI50 = 17 nM. When directly compared to selumetinib and mirdametinib in a subset of four MPNST cell lines, trametinib had the lowest mean GI50 (trametinib = 38 nM, mirdametinib = 1.6 µM, selumetinib = 4.9 µM). Trametinib was also superior to selumetinib and mirdametinib in blocking ERK1/2 phosphorylation for 24 h. Fimepinostat promoted cell death in all cell lines with a geometric mean GI50 = 17 pM. Conclusions: These studies demonstrate in vitro efficacy for two candidate MPNST therapeutics which could reduce tumor burden and metastasis in NF1 patients.

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