Factors that are intrinsic to therapy resistance other than MGMT, involve the dynamics of tumor evolution driven by inter- and intra-tumor heterogeneity, development of a high tumor mutation burden resulting in hypermutated tumors, metabolic changes that occur due to manipulation of free radical signaling and oncogenic splicing pathways preferentially expressed in therapy resistant GBM tumors as compared to the normal brain. The gene discussed is MGMT; the disease is neoplasm.