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|Authors||Keigo Amari, Yuki Toda, Shigekuni Hosogi, Toshihiko Imamura and Eishi Ashihara|
|Title||Abstract 643: Cdk4/6 inhibitor Abemaciclib overcomes resistance to BET inhibitor in leukemic cells with MLL-AF5q31 fusion gene|
|Abstract Text||Mixed-lineage leukemia (MLL)-related leukemia which has MLL rearrangement is an intractable disease. Recently, bromodomain and extra-terminal (BET) inhibitors are promising agents, and clinical trials are undergone. However, drug resistance against BET inhibitors has been reported, therefore, it is important to elucidate its mechanism. In this study, we established OTX015-resistant leukemic cells with MLL-AF5q31 fusion gene (OTX015-R cells) and identified molecules that contribute to drug resistance. In addition, we evaluated whether identified molecules are effective as therapeutic target for BET inhibitor-resistant MLL-related leukemia. To generate OTX015-R cell line, we cultured MLL-AF5q31 cells in the complete medium containing OTX015 with stepwise increasing concentrations. OTX015-R cells exhibited cross-resistance to various BET inhibitors. In addition, protein expressions of bromodomain-containing protein 4 (Brd4) and Brd4-regulated molecules c-Myc, Cdk6 and Bcl-2 were remarkably increased in OTX015-R cells compared with the parental cells. Furthermore, treatment of Cdk4/6 inhibitor Abemaciclib showed a significant antitumor effect on OTX015-R cells and protein expressions of Brd4 and Brd4-regulated molecules were decreased after Abemaciclib treatment. Abemaciclib exhibits antitumor effects on the parental MLL-AF5q31 cells by induction of cell cycle arrest. On the other hand, interestingly, apoptosis in the OTX015-R cells was induced without cell cycle arrest. These results suggest that Abemaciclib induces apoptosis in OTX015-R cells by another mechanism different from cell cycle regulation. We are going to clarify this mechanism. In conclusion, BET inhibitor-resistant MLL-AF5q31 cells upregulated expression levels of BRD4 and its downstream molecules. We suggest that Cdk6 is a potent therapeutic target for BET inhibitor-resistant MLL-related leukemias.|
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|KMT2A - AFF4||leukemia||predicted - sensitive||Abemaciclib||Preclinical - Cell culture||Actionable||In a preclinical study, treatment with Verzenio (abemaciclib) induced apoptosis, reduced expression of Brd4 and Brd4-regulated proteins, including c-Myc, Cdk6, and Bcl-2, and resulted in an anti-tumor effect by inducing cell cycle arrest in leukemia cells harboring a KMT2A-AFF4 fusion that had developed resistance to Birabresib (OTX015) in culture (Cancer Res 2020;80(16 Suppl):Abstract nr 643.)||detail...|