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DNA abasic sites act as rational therapeutic targets to synergize temozolomide response in both MMR-proficient and

Achyut Bora1,2, Ritesh Pal1,2, Chandra Sova Mandi1

  • 1Nucleic Acids Research Laboratory, Organic and Medicinal Chemistry Division, CSIR- Indian Institute of Chemical Biology 4, Raja S.C. Mullick Road, Kolkata 700032, West Bengal, India.

NAR Cancer
|July 26, 2024
PubMed

Insights

Targeting DNA abasic sites with RA-1 enhances temozolomide (TMZ) cancer therapy. This combination overcomes resistance by inducing DNA damage and apoptosis in mismatch-repair deficient and proficient cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Temozolomide (TMZ) resistance limits its efficacy, especially in mismatch-repair (MMR) deficient cancers.
  • The Base Excision Repair (BER) pathway influences TMZ response by processing DNA damage.
  • DNA abasic sites accumulate with increasing TMZ concentrations, suggesting they are key targets.

Purpose of the Study:

  • To investigate the role of DNA abasic sites in TMZ resistance.
  • To evaluate the efficacy of amino-quinoxaline small molecule RA-1 in targeting these sites.
  • To explore the synergistic effect of combining TMZ with RA-1.

Main Methods:

  • In vitro cleavage assays of TMZ-induced DNA abasic sites by RA-1.
  • Cellular studies on MMR-proficient and deficient cancer cells treated with TMZ and/or RA-1.
  • Analysis of DNA damage response pathways (ATM/ATR, Chk1/Chk2) and cell cycle arrest.

Main Results:

  • RA-1 selectively binds and cleaves TMZ-induced DNA abasic sites.
  • The combination of TMZ and RA-1 demonstrated significant synergistic anti-cancer effects in both MMR-proficient and deficient cells.
  • Synergy resulted from impaired BER, increased DNA double-strand breaks, and activation of ATM-Chk2/ATR-Chk1 pathways, leading to S-phase arrest and apoptosis.

Conclusions:

  • Targeting DNA abasic sites is a viable strategy to enhance TMZ efficacy.
  • RA-1 shows promise as an adjuvant therapy to overcome TMZ resistance.
  • The findings support the development of therapies that exploit the BER pathway to improve cancer treatment outcomes.

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