p53 Mutation: Critical Mediator of Therapy Resistance against Tumor Microenvironment

GBM, a grade IV glioma classified by World Health Organization, is considered highly malignant, vascular and invasive subtype. Hypoxia and neovascularization are signature histopathologic features of GBM, which is most lethal during first year after initial diagnosis despite surgical resection and other standard therapies. Temozolomide chemotherapy andradiotherapy against GBM tumor cells have led to a significant improvement intumor growth and patient survival in newly diagnosed and recurrent GBM. The survival advantage conferred by temozolomide chemotherapy is associated with methylation of the promoter region of the gene encoding O6-methylguanine DNAmethyltransferase (MGMT). Both tumor protein p53 (TP53) and MGMT are involved in DNA repair after chemotherapy or radiotherapy, which may contribute to drug resistance. In addition, tumor cells acquiring several mutations during tumor progression could contribute to therapy resistance in GBM.

Many different types of cancer including GBM show a high incidence of TP53 mutations, leading to the stabilization and overexpression ofmutant p53 proteins. Mutant p53 have both lost wild-type p53 tumor suppressor activity and gained functions that help to contribute to tumor progression .