Abstract
Patients with advanced biliary tract cancer (BTC) inevitably experience progression after first-line, gemcitabine-based chemotherapy, due to chemo-resistance. The genetic alterations of DNA damage repair (DDR) genes are usually determined in BTC tumors. In this study, we found that the POLQ mRNA levels are downregulated and the ataxia-telangiectasia mutated (ATM) inhibitor AZD0156 was more sensitive in gemcitabine-resistant BTC sublines than in the parental cell lines. The knockdown of DNA polymerase θ does not affect cell proliferation, but its combination with the ATM inhibitor facilitated cell death in gemcitabine-resistant and gemcitabine-intensive BTC cells. Moreover, in the DNA damage caused by photon, hydrogen peroxide, or chemotherapy drugs, synthetic lethal interactions were found in combination with ATM inhibition by AZD0156 and DNA polymerase θ depletion, resulting in increased DNA damage accumulation and micronucleus formation, as well as reduced cell survival and colony formation. Collectively, our results reveal that ATM acts as a potential target in gemcitabine-resistant and DNA polymerase θ-deficient BTC.
Highlights
For patients with advanced biliary tract cancer (BTC), cisplatin (CDDP) and gemcitabine (GEM) are typically used as the first-line chemotherapy
Among them are several genes with genomic alterations involved in DNA damage repair (DDR) systems, such as p53, KMT2C, ataxia-telangiectasia mutated (ATM), and ATR
DNA damage repair (DDR) deficiency is usually detected in different cancers, including BTC [1]
Summary
For patients with advanced biliary tract cancer (BTC), cisplatin (CDDP) and gemcitabine (GEM) are typically used as the first-line chemotherapy. DNA damage repair (DDR) deficiency is usually detected in different cancers, including BTC [1]. DNA polymerase θ, encoded by POLQ, is an enzyme that is involved in alternative, non-homologous end-joining (alt-NHEJ). A combination of atm deficiency and polq loss-of-function background caused synthetic semi-lethality, and the few surviving mice displayed increased chromosomal instability [12]. The increased sensitivity of the ATM inhibitor (AZD0156) was observed in gemcitabine-resistant cells, and AZD0156 alone enhanced cell death in DNA polymerase θ knockdown cells. These observations provide valuable evidence of novel therapeutic strategies for advanced BTC patients
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