Reference - Detail
| RRC ID | 63171 |
|---|---|
| Author | Pan YR, Wu CE, Yeh CN. |
| Title | ATM Inhibitor Suppresses Gemcitabine-Resistant BTC Growth in a Polymerase θ Deficiency-Dependent Manner. |
| Journal | Biomolecules |
| 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. |
| Volume | 10(11) |
| Published | 2020-11-9 |
| DOI | 10.3390/biom10111529 |
| PII | biom10111529 |
| PMID | 33182492 |
| PMC | PMC7697425 |
| MeSH | Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors* Biliary Tract Neoplasms / pathology* Cell Line, Tumor DNA-Directed DNA Polymerase / deficiency* DNA-Directed DNA Polymerase / genetics Deoxycytidine / analogs & derivatives* Deoxycytidine / pharmacology Drug Resistance, Neoplasm / drug effects* Gemcitabine Gene Knockdown Techniques Humans Protein Kinase Inhibitors / pharmacology* |
| IF | 4.082 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 1 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | RBE(RCB1292) HuCCT1(RCB1960) SSP-25(RCB1293) TGBC24TKB(RCB1196) TFK-1(RCB2537) |