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Oncotarget: ATR inhibition reverses the resistance of cancer cells to temozolomide


FOR IMMEDIATE RELEASE
2021-10-29

Oncotarget published "ATR inhibition reverses the resistance of homologous recombination deficient MGMTlow/MMRproficient cancer cells to temozolomide" which reported that the therapeutic efficacy of temozolomide is hindered by inherent and acquired resistance.

The authors observed that only 31% of MGMTlow/?ve/MMRproficient patient-derived and established cancer lines are sensitive to TMZ at clinically relevant concentrations. TMZ treatment resulted in DNA damage signaling in both sensitive and resistant lines, but prolonged G2/M arrest and cell death were exclusive to sensitive models. This suggests that HR defects and low REV3L levels could be useful selection criteria for enhanced clinical efficacy of an ATRi plus TMZ combination.

This suggests that HR defects and low REV3L levels could be useful selection criteria for enhanced clinical efficacy of an ATRi plus TMZ combination

Dr. Annamaria Rapisarda from Leidos Biomedical Research Inc. said, "Temozolomide (TMZ) is a DNA alkylating agent that is approved for standard-of-care of glioblastoma and is a clinical standard-of-care for advanced melanoma, respectively."

TMZ is currently being evaluated in combination with other agents in >300 clinical trials targeting solid tumors. Twenty five percent of these trials involve cancers unrelated to melanomas and gliomas specifically and brain cancers in general and include breast, pancreatic, colorectal as well as lung cancers, suggesting an increased interest in the evaluation of TMZ efficacy across a multitude of cancers. Together DDR and DDT are pivotal for completing replication and preventing fork breakage, which averts the formation of cytotoxic double-strand breaks and genomic instability.

Figure 4: α1,2-mannosidase expression patterns in cancer. Mice harboring (A?B) BL0382 or (C?D) LG0520 tumor fragments were treated for 2 cycles with vehicle, TMZ (50 mg/kg; QDx5, 2 days rest), VE822 (45 mg/kg; QDx4, 3 days rest) or TMZ + VE822. Treatments were administered between days 22 and 33 (BL0382) or days 28 and 39 (LG0520). (A, C) Mean tumor volume SD is shown (*p < 0.05 by the Holm-Sidak method). (B?D) Survival graphs for PDXs (B) BL0382 and (D) LG0520. Arrowheads depict the end of treatment.

DDR can promote the recovery of stalled replication forks through a regulated process primarily controlled by the replication checkpoint kinase ATR. Low-fidelity polymerases, such as Pol, Pol, Pol, Pol, and REV1, are key players in TLS and several reports indicate that their overexpression enhances DDR, resulting in resistance to DNA damaging therapy.

Two biomarkers, MGMT epigenetic silencing, which is correlated with TMZ responsiveness and MMR deficiency, which is correlated with TMZ resistance in the absence of MGMT, have been evaluated clinically with limited success.

The Rapisarda Research Team concluded in their Oncotarget Research Output that recently Jackson et al. reported that TMZ further sensitizes MGMT?ve cell lines to ATRi and pinpointed MGMT negativity as a biomarker for predicting the effectiveness of TMZ + ATRi in lines that are moderately sensitive to TMZ. However, these authors have further identified HR defects and DDT deficiencies as additional predictors/biomarkers for the efficacy of this combination.

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DOI - https://doi.org/10.18632/oncotarget.28090

Full text - https://www.oncotarget.com/article/28090/text/

Correspondence to - Annamaria Rapisarda - rapisardaa@mail.nih.gov

Keywords - TMZ, MMR, ATR, HR, REV3L

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