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Oncotarget: ATM inhibition overcomes resistance to histone deacetylase inhibitor


The cover for issue 37 of Oncotarget features Figure 7, "The combination of romidepsin and KU60019 is synergistic in a xenograft model of MCL," by Scotto, et al. which reported that the antiproliferative effect induced by histone deactylase inhibitors 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.

HDAC inhibitors appear to activate p21 expression via ataxia telangiectasia mutated activity.

The Oncotarget authors 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.

Dr. Owen A. O'Connor from The Columbia University Medical Center said, "HDAC inhibitors (HDACi) have emerged as valuable drugs in the treatment of select lymphomas and synergize with a diverse range of pharmacological and biological agents."

The observation leads to the following hypothesis: if induction of p21 compromises the efficacy of HDAC inhibitors, then strategies to mitigate HDAC inhibitor induced p21 expression could lead to promising synergistic combinations.

Induction of p21 by HDAC inhibitors is compromised in A-T cells given that ATM activity is essential for HDAC inhibitor-induced p21 expression.

Figure 7: The combination of romidepsin and KU60019 is synergistic in a xenograft model of MCL. (A) The in vivo therapeutic efficacy of romidepsin and KU60019 as single agents and combination was evaluated using a SCID Beige xenograft mouse model of MCL. The effectiveness of romidepsin in combination with KU60019 was evaluated in a 3 week cycle administration. Romidepsin was administered weekly at days 1, 8, and 15. KU60019 was given at days 1, 2, 3, 4, and 5 of each week. The data are expressed as average tumor volume (mm3) per group as a function of time. A two-tailed t test confirmed that combination was statistically superior to both the single agents and the control in inhibiting tumor growth (0.001 < P < 0.05). (B) Statistical analysis of survival following the 3 weeks administration cycle. When compared to control, only the romidepsin plus KU60019 combination was statistically significant. P-value, standard error of the mean (SEM), coefficient of determination (R squared), and coefficient of correlation (r) of comparisons.

Collectively, these observations have led to the following hypothesis: If ATM activity is necessary for HDAC inhibitor mediated p21 induction, then selective ATM inhibitors could mitigate the HDAC induced p21 expression and potentiate its cytotoxic effect.

The ATM inhibitor nullifies HDAC induction of p21 expression resulting in a synergistic interaction.

KU60019 reduces p21 expression at the transcriptional level and antagonizes romidepsin transcriptional induction of p21. In both instances, the result is a markedly down-regulation of p21 expression at the protein level.

The O'Connor Research Team concluded in their Oncotarget Research Paper that it is intuitive that pleotropic drugs like HDACi are likely to have both favorable and unfavorable effects on cell growth and survival.

The O'Connor Research Team concluded in their Oncotarget Research Paper that it is intuitive that pleotropic drugs like HDACi are likely to have both favorable and unfavorable effects on cell growth and survival.

Strategies directed toward understanding how to mitigate the unfavorable influences of the class can lead to improved efficacy in rational combinations.

Many examples of drug synergy with HDAC inhibitors have been driven by random efforts in mixing and matching in order to identify possible complementary partners.

Obviously, a clear understanding of the molecular pharmacologic features of pleotropic drug classes like HDAC inhibitors can afford unique opportunities to think about logical combinations.

Ultimately, these approaches need to be translated to the clinic in order to establish therapeutic merit in the clinic.

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DOI - https://doi.org/10.18632/oncotarget.27723

Full text - https://www.oncotarget.com/article/27723/text/

Correspondence to - Owen A. O'Connor - owenaoconnor@gmail.com

Keywords - lymphoma, HDAC inhibitor, ATM inhibitor, p21, cell cycle

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