Inhibition of DNA-repair genes Ercc1 and Mgmt enhances temozolomide efficacy in gliomas treatment: a pre-clinical study

Abstract

Gliomas are the most common primary brain tumors. To date, therapies do not allow curing patients, and glioblastomas (GBMs) are associated with remarkably poor prognosis. This situation is at least partly due to intrinsic or acquired resistance to treatment, especially to chemotherapy. In 2005, temozolomide (TMZ) has become the first chemotherapeutic drug validated for GBM. Nevertheless TMZ efficacy depends on Mgmt status. While the methylation of Mgmt promoter was considered so far as a prognostic marker, its targeting is becoming an effective therapeutic opportunity. Thus, arrival of both TMZ and Mgmt illustrated that considerable progress can still be realized by optimizing adjuvant chemotherapy. A part of this progress could be accomplished in the future by overcoming residual resistance. The aim of the present study was to investigate the involvement of a set of other DNA-repair genes in glioma resistance to temozolomide. We focused on DNA-repair genes located in the commonly deleted chromosomal region in oligodendroglioma (1p/19q) highly correlated with patient response to chemotherapy. We measured effects of inhibition of ten DNA-repair genes expression using siRNAs on astrocytoma cell response to cisplatin (CDDP) and TMZ. SiRNAs targeting ercc1, ercc2, mutyh, and pnkp significantly sensitized cells to chemotherapy, increasing cell death by up to 25%. In vivo we observed a decrease of subcutaneous glioma tumor growth after injection of siRNA in conjunction with absorption of TMZ. We demonstrated in this pre-clinical study that targeting of DNA-repair genes such as Ercc1 could be used as an adjuvant chemosensitization treatment, similarly to Mgmt inhibition.

Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas

“…Resistance mechanisms that lead to tumor progression during alkylator therapy include the repair of TMZ-induced monofunctional alkylation and single strand DNA lesion by methyl-guanyl methyltransferase (MGMT) and repair of double stranded DNA breaks (DSB) by specific DNA repair enzymes in glioma cells and in GSCs (42). Consequently, therapeutic strategies that can potentiate the activity of TMZ are of high clinical relevance.…”

Linc00152 Functions as a Competing Endogenous RNA to Confer Oxaliplatin Resistance and Holds Prognostic Values in Colon Cancer

“…On the other hand, activation of the AKT signaling pathway decreased the sensitivity of cells to L-OHP induced apoptosis in 1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97 101 105 109 113 117 121 125 129 These results demonstrated that Linc00152 contributed to L-OHP resistance at least in part through modulating the miR-193a-3p/ ERBB4/AKT axis. In colon cancer, biomarkers associated with L-OHP resistance, for example, excision repair cross-complementing 1 protein (ERCC1) and G-protein-coupled receptor galanin receptor 1 (GalR 1), have been reported, 50,51 revealing useful targets of L-OHP resistance are clinically important. Nevertheless, these findings have failed to translate to clinical practice and optimal prognostic biomarkers for L-OHP-based chemotherapy have not been established up to now.…”

DNA repair genes in astrocytoma tumorigenesis, progression and therapy resistance

“…It was also shown that the disruption of Ape1 (Bobola et al, 2001) or DNA polymerase b (Trivedi et al, 2008) activity sensitizes cells to TMZ. Moreover, increased NER activity was detected after treatment with TMZ (Nagel et al, 2017), while downregulation of ERCC1 promoted higher sensitivity to TMZ treatment, similarly to MGMT inhibition (Boccard et al, 2015).…”

“…The list of significant biomarkers is growing in an astonishing manner and includes a wide range of molecules such as lncRNAs and microRNAs (e.g. HOTAIR and miR-141), and several DNA repair genes (Boccard et al, 2015;Bian et al, 2016;Reon et al, 2016), which are importantly correlated with genome stability and will be explored in more detail in the next sections. Table 3 summarizes the main DNA repair biomarkers discussed in this review.…”