Plasma cells in malignant peripheral nerve sheath tumor response to kinase inhibitor therapy and immune checkpoint blockade

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are lethal, Ras-driven sarcomas that fail to respond to chemotherapy and radiation. Immune checkpoint blockade (ICB) therapy has provided sustained anti-tumor activity for other cancers but it has disappointingly not yielded promising results as a monotherapy for MPNSTs. The only curative option for patients is complete surgical resection, which is difficult due to the location of the tumor along the nerve. Recent advances in the field have outlined how precursor lesions, plexiform neurofibromas (PNFs), transform into MPNSTs, providing key insight into potentially relevant therapies for patients. Working with a team of investigators at the University of Iowa, we evaluated patientmatched PNFs and MPNSTs to identify drug targets to test preclinically. We found that downstream effectors of Ras, MEK and Cyclin Dependent Kinases 4 and 6 (CDK4/6), are hyperactivated in MPNSTs and represent actionable clinical targets for the management of these aggressive tumors.