New insights into acquired temozolomide resistance in glioblastoma?

This scientific commentary refers to ‘c-Myc–miR-29c–REV3L signalling pathway drives the acquisition of temozolomide resistance in glioblastoma’ by Luo et al. (doi:10.1093/brain/awv287) emergence of tumour cell resistance to chemotherapy represents a major challenge for the development of durable therapeutic strategies across most solid cancers including glioblastoma, the most malignant primary brain tumour in adults. The standard of care for glioblastoma is maximum surgery as safely feasible followed by radiotherapy, with concomitant and maintenance chemotherapy with the alkylating agent temozolomide (TMZ/RT→TMZ). This results in a median overall survival in the range of 12 months on a population level (Weller et al. , 2014). Radiotherapy alone doubled median survival in early studies, but the best radiological response is commonly stable disease, progression is inevitable, and the efficacy of radiotherapy may be partly related to anti-angiogenic rather than intrinsic tumour cell cytotoxic effects. Mechanisms underlying resistance to radiotherapy remain poorly understood, but extensive hypoxia may be an important factor.TMZ was approved for the treatment of newly diagnosed glioblastoma because of a moderate prolongation of median survival (Stupp et al. , 2005). Subgroup analyses revealed that the benefit from TMZ was largely restricted to patients with glioblastomas that exhibit a particular epigenetic alteration, promoter methylation of the O6-methylguanine DNA methyltransferase ( MGMT ) gene (Hegi et al. , 2005). However, even these patients eventually all progress and succumb to their disease, in the absence of changes in MGMT promoter methylation …