Epigenetic silencing of HTATIP2 in glioblastoma contributes to treatment resistance by enhancing nuclear translocation of the DNA repair protein MPG.

Glioblastoma, the most malignant brain tumor in adults, exhibits characteristic patterns of epigenetic alterations that await elucidation. The DNA methylome of glioblastoma revealed recurrent epigenetic silencing of HTATIP2, which encodes a negative regulator of importin ß-mediated cytoplasmic-nuclear protein translocation. Its deregulation may thus alter the functionality of cancer-relevant nuclear proteins, such as the base excision repair (BER) enzyme N-methylpurine DNA glycosylase (MPG), which has been associated with treatment resistance in GBM. We found that induction of HTATIP2 expression in GBM cells leads to a significant shift of predominantly nuclear to cytoplasmic MPG, whereas depletion of endogenous HTATIP2 results in enhanced nuclear MPG localization. Reduced nuclear MPG localization, prompted by HTATIP2 expression or by depletion of MPG, yielded less phosphorylated-H2AX-positive cells upon treatment with an alkylating agent. This suggested reduced MPG-mediated formation of apurinic/apyrimidinic sites, leaving behind unrepaired DNA lesions, reflecting a reduced capacity of BER in response to the alkylating agent. Epigenetic silencing of HTATIP2 may thus increase nuclear localization of MPG, thereby enhancing the capacity of the glioblastoma cells to repair treatment-related lesions and contributing to treatment resistance.

Epidermal growth factor receptor: a re-emerging target in glioblastoma.

PURPOSE OF REVIEW: Amplification and overexpression of the epidermal growth factor receptor (EGFR) gene are a hallmark of primary glioblastoma (45%), making it a prime target for therapy. In addition, these amplifications are frequently associated with oncogenic mutations in the extracellular domain. However, efforts at targeting the EGFR tyrosine kinase using small molecule inhibitors or antibodies have shown disappointing efficacy in clinical trials for newly diagnosed or recurrent glioblastoma. Here, we review recent insights into molecular mechanisms relevant for effective targeting of the EGFR pathway. RECENT FINDINGS: Molecular workup of glioblastoma tissue of patients under treatment with small molecule inhibitors has established drug concentrations in the tumor tissue, and has shed light on the effectiveness of target inhibition and respective effects on pathway signaling. Further, functional analyses of interaction of small molecule inhibitors with distinct properties to bind to the active or inactive form of EGFR have provided new insights that will impact the choice of drugs. Finally, vaccination approaches targeting the EGFRvIII mutant featuring a tumor-specific antigen have shown promising results that warrant larger controlled clinical trials. SUMMARY: A combination of preclinical and clinical studies at the molecular level has provided new insights that will allow refining strategies for targeting the EGFR pathway in glioblastoma.