Reference Detail

Ref Type

PMID

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Res	80	16 Suppl	2020

URL

https://cancerres.aacrjournals.org/content/80/16_Supplement/643.short

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References