論文 - 詳細
| RRC ID | 73375 |
|---|---|
| 著者 | Hiroki H, Akahane K, Inukai T, Morio T, Takagi M. |
| タイトル | Synergistic effect of combined PI3 kinase inhibitor and PARP inhibitor treatment on BCR/ABL1-positive acute lymphoblastic leukemia cells. |
| ジャーナル | Int J Hematol |
| Abstract |
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) function by inhibiting base excision repair and inducing synthetic lethality in homologous recombination repair-deficient cells, such as BRCA1/2-mutated cancer cells. The BCR/ABL1 fusion protein causes dysregulated cell proliferation and is responsible for chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). BCR/ABL1 also induces genomic instability by downregulating BRCA1. We investigated the effect of the PARPi, olaparib, against Ph+ALL cell lines and found that they show variable sensitivity, presumably due to cancer-associated genetic alterations other than BCR/ABL1. To investigate the reasons for the variable responses of Ph+ALL cells to PARPi treatment, we analyzed the transcriptomes of olaparib-sensitive and -resistant Ph+ALL cell lines, which revealed that activation of the phosphatidylinositol 3-kinase (PI3K) pathway was a hallmark of PARPi resistance. Based on these findings, we examined the effects of adding a PI3K inhibitor (PI3Ki) to PARPi treatment to overcome PARPi insensitivity in Ph+ALL cell lines. Combination with PI3Ki increased PARPi cytotoxicity in PARPi-resistant Ph+ALL cell lines. Tyrosine kinase inhibitor (TKI) therapy is the gold standard for Ph+ALL, and, based on our findings, we propose that PARPi combined with TKI and PI3K inhibition could be a novel therapeutic strategy for Ph+ALL. |
| 巻・号 | 117(5) |
| ページ | 748-758 |
| 公開日 | 2023-5-1 |
| DOI | 10.1007/s12185-022-03520-8 |
| PII | 10.1007/s12185-022-03520-8 |
| PMID | 36575328 |
| MeSH | Antineoplastic Agents* / pharmacology BRCA1 Protein / genetics BRCA2 Protein Cell Line, Tumor Drug Resistance, Neoplasm / genetics Fusion Proteins, bcr-abl Humans Phosphatidylinositol 3-Kinases / metabolism Poly(ADP-ribose) Polymerase Inhibitors / pharmacology Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use Precursor Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy Precursor Cell Lymphoblastic Leukemia-Lymphoma* / genetics Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use |
| IF | 2.245 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Rat-1(RCB1830) |