Temozolomide (TMZ) is a powerful chemotherapeutic drug that is currently approved to treat brain cancer (glioblastoma, GBM) and advanced melanoma. TMZ has a remarkably precise molecular target—the O-6 position of guanine—and is capable of inducing DNA damage. This prodrug can elicit many responses in a variety of cancer cells, including cell death, autophagy and senescence. At present, there are over 300 clinical trials evaluating the efficacy of TMZ in combination with other agents in solid tumors. At least 25% of these trials include testing the efficacy of TMZ in breast, pancreatic, colorectal and lung cancers.

“Low MGMT levels in other types of cancer have resulted in the consideration of TMZ as a potential therapy beyond glioblastoma and melanoma.”

However, not all patients benefit from TMZ treatment, despite presenting with biomarkers known to predict TMZ treatment response, such as low O-6-Methylguanine-DNA methyltransferase (MGMTlow) and proficient DNA mismatch repair (MMRproficient). Researchers have found in some patients that the clinical efficacy of TMZ is hindered by inherent and acquired mechanisms of resistance.

In 2021, a team of researchers from Leidos Biomedical Research Inc. (the current operations and technical support contractor for the Frederick National Laboratory for Cancer Research) and the National Institutes of Health’s National Cancer Institute conducted a new study on TMZ. In an attempt to overcome TMZ resistance, they examined the in vitro and in vivo anti-tumor efficacy of TMZ when combined with ataxia telangiectasia and Rad3 related inhibitors (ATRi) and a wide variety of other inhibitor drugs. Their paper was published as the cover of Oncotarget’s Volume 12, Issue 21, and entitled, “ATR inhibition reverses the resistance of homologous recombination deficient MGMTlow/MMRproficient cancer cells to temozolomide.”

Full blog - https://www.impactjournals.com/journals/blog/oncotarget/new-study-atr-inhibition-reverses-chemo-resistance-in-subset-of-cells/

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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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