CHK1/2 as a potential therapeutic target in Neurofibromatosis type 2 Schwannomas

The Merlin protein, encoded by the tumor suppressor gene Neurofibromatosis type II (NF2), serves as a linker between the actin cytoskeleton, the plasma membrane receptors, and other intracellular signaling molecules. While there is a basic understanding of how Merlin regulates oncogenic signaling pathways, current targeted therapies have yet to demonstrate consistent clinical efficacy. Using a library of protein kinase inhibitors, we found that NF2-null Schwann cells (SCs) were uniquely sensitive to prexasertib, a drug that targets the DNA damage response pathway kinases CHK1/2 (Checkpoint Kinase 1 and 2). NF2-null SC proliferation was also sensitive to small molecule inhibitors of CHK1/2 downstream effectors. At baseline, NF2-null SCs have increased RAC1 activity, elevated levels of reactive oxygen species (ROS) production, and higher levels of DNA damage. Exposing NF2-null SCs to DNA damaging agents such as doxorubicin or carboplatin, alone or in combination with prexasertib, further decreased their proliferation. Consistent with this idea, suppressing RAC1 or NOX2 activity with small molecule inhibitors, decreased ROS production and restored resistance to prexasertib in NF2-null hSCs, suggesting that active RAC1 and high ROS render NF2-null hSC uniquely vulnerable to DNA damage. Furthermore, restoring NF2 expression in NF2-null Schwann cells restored their resistance to prexasertib, reduced RAC1 activity, and lowered levels of ROS and DNA damage. The intrinsic elevation of RAC1, ROS, and DNA damage in NF2-null hSCs suggest that inhibiting DNA damage response pathways might be clinically useful in patients with NF2-null schwannomas.