Error-prone translesion synthesis mediates acquired chemoresistance

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Cancer drug resistance is a major clinical challenge, hindering effective treatment of widespread cancers.
• The molecular basis for how initially drug-sensitive tumors acquire therapeutic resistance is not fully understood.
• Error-prone translesional DNA synthesis (TLS) contributes to mutations from anticancer drugs, but its role in tumor drug resistance is unclear.

Purpose of the Study:

• To investigate the role of error-prone translesional DNA synthesis (TLS) in chemotherapy-induced mutations.
• To determine if TLS is involved in the development of acquired resistance to chemotherapy in a mouse model of B-cell lymphoma.
• To explore the potential of targeting TLS as a dual anticancer strategy.

Main Methods:

• Utilized a mouse model of B-cell lymphoma.
• Administered chemotherapy agents like cisplatin and cyclophosphamide.
• Suppressed Rev1, a key protein in TLS.
• Performed repeated cycles of tumor engraftment and chemotherapy treatment.

Main Results:

• Suppression of Rev1 inhibited both cisplatin- and cyclophosphamide-induced mutagenesis.
• Rev1 was found to play a critical role in the acquisition of cyclophosphamide resistance.
• Chemotherapy not only selects for resistant cells but also promotes TLS-mediated acquisition of resistance mutations.

Conclusions:

• Chemotherapy can directly promote the acquisition of drug resistance through TLS-mediated mutations.
• Targeting TLS may offer a dual therapeutic benefit by sensitizing tumors to existing therapies and preventing the emergence of chemoresistance.
• Inhibiting Rev1 presents a potential strategy to overcome or prevent cancer drug resistance.