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Synergistic effects of combined BET and FAK inhibition against Vestibular Schwannomas in NF2-related Schwannomatosis. | LitMetric

AI Article Synopsis

  • Neurofibromatosis type 2 (NF2) is a rare condition leading to tumors like vestibular schwannomas and meningiomas, and currently lacks FDA approved medication.* -
  • Previous research shows that BET inhibition can slow the growth of NF2-related cells, and this study investigates whether combining both BET and FAK inhibition could enhance these effects.* -
  • Results indicate that this combination effectively halts the growth of NF2-null cells by disrupting their cell cycle and significantly downregulating FAK1, suggesting a promising new treatment approach for NF2-related tumors.*

Article Abstract

Neurofibromatosis type 2 (NF2) is a rare disorder that causes vestibular schwannomas (VS), meningiomas and ependymomas. To date, there is no FDA approved drug-based treatment for NF2. We have previously identified that BET inhibition can selectively reduce growth of the NF2-null schwannoma and Schwann cells in vitro and tumorigenesis in vivo and, separately, reported that inhibition of Focal Adhesion Kinase 1 (FAK1) via crizotinib has antiproliferative effects in NF2-null Schwann cells. The current study was aimed at determining whether combined BET and FAK inhibition can synergize and to identify the mechanisms of action. A panel of normal and NF2-null Schwann and schwannoma cell lines were used to characterize the effects of combined BET and FAK inhibition in vitro and in vivo using pharmacological and genetic approaches. The mechanism of action was explored by chromatin immunoprecipitation, ChIP-PCR, western blotting, and functional approaches. We find that combined BET and FAK inhibition are synergistic and inhibit the proliferation of NF2-null schwannoma and Schwann cell lines in vitro and in vivo, by arresting cells in the G1/S and G2/M phases of the cell cycle. Further, we identify the mechanism of action through the downregulation of FAK1 transcription by BET inhibition, which potentiates inhibition of FAK by 100-fold. Our findings suggest that combined targeting of BET and FAK1 may offer a potential therapeutic option for the treatment of NF2-related schwannomas.

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Source
http://dx.doi.org/10.1038/s41388-024-03144-8DOI Listing

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