Our findings raise concern that EZH2 inhibition by drugs such as tazemetostat, either alone or in combination with other agents such as the EGFR inhibitor panitumumab or the proteasome inhibitor bortezomib, as used in our case, may increase the risk of CNS metastasis through glial mimicry in INI1-deficient tumors such as RMC and epithelioid sarcoma. The gene discussed is SMARCB1; the disease is epithelioid sarcoma.