![]() One of the key challenges in treating glioblastoma is the ability of cancer cells to evade the effects of chemotherapy and radiation therapy. In fact, GB remains a difficult-to-treat cancer due to the high degree of inter- and intra-tumour heterogeneity and the complexity of genetic, epigenetic and microenvironment events. Patients with methylated MGMT (O6-methylguanine-DNA methyltransferase) promoter respond with better outcome to TMZ treatment given the role of MGMT in DNA damage repair, which highlights the relevance of epigenomic cues in the patient outcome upon treatment. Temozolomide (TMZ) is a DNA alkylating agent commonly used in the treatment of glioblastoma as adjuvant to radiotherapy. Hence, the current standard of care for GB patients consists of radiotherapy and concomitant chemotherapy with temozolomide (TMZ), often preceded by tumour debulking surgery. ![]() While the addition of tumour-treating fields (TTFields) following chemoradiotherapy has led to extended survival, the treatment is not widely available due largely to cost-efficiency concerns, and in the countries where it is applied, only 30% of patients are eligible and therefore receive this treatment option. Due to its highly invasive nature, complete surgical resection is nearly impossible and therefore recurrence is inevitable. Glioblastoma (GB), also known as grade 4 astrocytoma, is a common and highly aggressive type of primary brain tumour, for which survival rates have not significantly improved in recent decades (median survival ~ 14 months, 5-year survival < 5%). This study demonstrates how CRISPR/Cas9-based perturbation of enhancers can be used to modulate the expression of key cancer genes, which can help improve the effectiveness of existing cancer treatments and potentially the prognosis of difficult-to-treat cancers such as glioblastoma. Our findings demonstrate how epigenomic perturbation of EGFR enhancers can ameliorate the aggressiveness of glioblastoma cells and enhance the efficacy of TMZ treatment. Moreover, EGFR enhancer -perturbation increases the sensitivity of GB cells to TMZ, the first-choice chemotherapeutic agent to treat glioblastoma. ![]() ResultsĮpigenomic perturbation of the EGFR regulatory region decreases EGFR expression and reduces the proliferative and invasive capacity of glioblastoma cells, which also undergo a metabolic reprogramming in favour of mitochondrial respiration and present increased apoptosis. We used CRISPR/Cas9-based approaches to target the EGFR enhancer regions, generating multiple modified GB cell lines, which enabled us to study the functional response to enhancer perturbation. Here, we investigated the influence of the EGFR regulatory genome on GB cells and identified novel EGFR enhancers located near the GB-associated SNP rs723527. ![]() Alterations in the Epidermal Growth Factor Receptor gene ( EGFR) are common in GB tumours, but therapies targeting EGFR have not shown significant clinical efficacy. Patients typically rely on radiotherapy with concurrent temozolomide (TMZ) treatment and face a median survival of ~ 14 months. Glioblastoma (GB) is the most aggressive of all primary brain tumours and due to its highly invasive nature, surgical resection is nearly impossible.
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