Oncotarget

Research Papers:

ATM inhibition overcomes resistance to histone deacetylase inhibitor due to p21 induction and cell cycle arrest

Luigi Scotto, Xavier J. Serrano, Kelly Zullo, Cristina Kinahan, Changchun Deng, Ahmed Sawas, Susan Bates and Owen A. O’Connor _

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Oncotarget. 2020; 11:3432-3442. https://doi.org/10.18632/oncotarget.27723

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Abstract

Luigi Scotto1, Xavier J. Serrano1, Kelly Zullo1, Cristina Kinahan1, Changchun Deng1,2, Ahmed Sawas2, Susan Bates3 and Owen A. O’Connor1,2

1 Division of Experimental Therapeutics, Department of Medicine, Columbia University Medical Center, New York, NY, USA

2 Center for Lymphoid Malignancies, Department of Medicine, Columbia University Medical Center, New York, NY, USA

3 Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, New York, NY, USA

Correspondence to:

Owen A. O'Connor,email: owenaoconnor@gmail.com

Keywords: lymphoma; HDAC inhibitor; ATM inhibitor; p21; cell cycle

Received: March 14, 2020     Accepted: June 20, 2020     Published: September 15, 2020

ABSTRACT

The antiproliferative effect induced by histone deactylase inhibitors (HDACi) is associated with the up-regulated expression of the cyclin-dependent kinase inhibitor p21. Paradoxically, the increased expression of p21 correlates with a reduced cell killing to the drug. The direct targeting of p21 is not feasible. An alternate approach could selectively target factors upstream or downstream of p21 that affect one or more specific aspects of p21 function. HDAC inhibitors appear to activate p21 expression via ataxia telangiectasia mutated (ATM) activity. KU60019, a specific ATM inhibitor, has shown to decrease the p21 protein levels in a concentration dependent manner. We explored the potential synergistic interaction of the ATM inhibitor with romidepsin, given the potential complementary impact around p21. A synergistic cytotoxic effect was observed in all lymphoma cell lines examined when the HDACi was combined with KU60019. The increase in apoptosis correlates with decreased expression of p21 due to the ATM inhibitor. KU60019 decreased expression of the cyclin-dependent kinase inhibitor at the transcriptional level, compromising the ability of HDACi to induce p21 and cell cycle arrest and ultimately facilitating a shift toward the apoptotic phase. Central to the increased apoptosis observed when romidepsin is combined with KU60019 is the reduced expression of p21 and the absence of a G2/M cell cycle arrest that would be exploited by the tumor cells to evade the cytotoxic effect of the HDAC inhibitor. We believe this strategy may offer a promising way to identify rational combinations for HDACi directed therapy, improving their activity in malignant disease.


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