1. Academic Validation
  2. OGG1 co-inhibition antagonizes the tumor-inhibitory effects of targeting MTH1

OGG1 co-inhibition antagonizes the tumor-inhibitory effects of targeting MTH1

  • Redox Biol. 2021 Apr;40:101848. doi: 10.1016/j.redox.2020.101848.
Ling Zhang 1 Laura Misiara 2 Govindi J Samaranayake 3 Nisha Sharma 2 Dao M Nguyen 4 Yu-Ki Tahara 5 Eric T Kool 5 Priyamvada Rai 6
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, University of Miami Medical School, FL 33136, USA.
  • 2 College of Arts and Sciences, University of Miami, FL 33146, USA.
  • 3 Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Medical School, FL 33136, USA.
  • 4 Department of Surgery, University of Miami Medical School, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
  • 5 Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
  • 6 Department of Radiation Oncology, University of Miami Medical School, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA. Electronic address: prai@med.miami.edu.
Abstract

Cancer cells develop protective adaptations against oxidative DNA damage, providing a strong rationale for targeting DNA repair proteins. There has been a high degree of recent interest in inhibiting the mammalian Nudix pyrophosphatase MutT Homolog 1 (MTH1). MTH1 degrades 8-oxo-dGTP, thus limiting its incorporation into genomic DNA. MTH1 inhibition has variously been shown to induce genomic 8-oxo-dG elevation, genotoxic strand breaks in p53-functional cells, and tumor-inhibitory outcomes. Genomically incorporated 8-oxo-dG is excised by the base excision repair Enzyme, 8-oxo-dG glycosylase 1 (OGG1). Thus, OGG1 inhibitors have been developed with the idea that their combination with MTH1 inhibitors will have anti-tumor effects by increasing genomic oxidative DNA damage. However, contradictory to this idea, we found that human lung adenocarcinoma with low OGG1 and MTH1 were robustly represented in patient datasets. Furthermore, OGG1 co-depletion mitigated the extent of DNA strand breaks and cellular senescence in MTH1-depleted p53-wildtype lung adenocarcinoma cells. Similarly, shMTH1-transduced cells were less sensitive to the OGG1 inhibitor, SU0268, than shGFP-transduced counterparts. Although the dual OGG1/MTH1 inhibitor, SU0383, induced greater cytotoxicity than equivalent combined or single doses of its parent scaffold MTH1 and OGG1 inhibitors, IACS-4759 and SU0268, this effect was only observed at the highest concentration assessed. Collectively, using both genetic depletion as well as small molecule inhibitors, our findings suggest that OGG1/MTH1 co-inhibition is unlikely to yield significant tumor-suppressive benefit. Instead such co-inhibition may exert tumor-protective effects by preventing base excision repair-induced DNA nicks and p53 induction, thus potentially conferring a survival advantage to the treated tumors.

Keywords

MTH1 inhibition; OGG1 inhibition; lung cancer; oxidative DNA damage; p53; senescence.

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