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Experimental and Molecular Therapeutics

Abstract #4598: Inhibition of ATM sensitizes cells to the topoisomerase I inhibitor SN38

Kristen Garner, Ryan Montano and Alan Eastman
Kristen Garner
Dartmouth Medical School, Lebanon, NH
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Ryan Montano
Dartmouth Medical School, Lebanon, NH
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Alan Eastman
Dartmouth Medical School, Lebanon, NH
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DOI:  Published May 2009
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AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Abstract

Many anticancer agents induce DNA damage that activates checkpoints to arrest cell cycle progression. The arrest provides time for DNA repair so that the cells can survive. Abrogating these checkpoints is an attractive strategy to sensitize tumors to DNA-damaging agents as it should increase DNA damage and cell death. The topoisomerase I inhibitor SN38 arrests cells in G2 phase at low concentrations or S phase at higher concentrations. This arrest occurs at concentrations of SN38 that activate Chk1 (1-10 ng/ml). The Chk1 inhibitor UCN-01 can overcome this arrest and drive cells through S, G2 and a lethal mitosis. However, in long term growth or cytotoxicity assays, UCN-01 had negligible impact on the overall level of cell death. At very low concentrations of SN38 (0.03-0.3 ng/ml), there is no apparent activation of Chk1 nor cell cycle arrest. We now report that inhibition of ATM using KU55933 can dramatically enhance cell killing at these very low concentrations of SN38. Neither KU55933 alone, low levels of SN38, nor the combination decrease the rate of progression through S phase, but the combination induces arrest in G2 and the cells subsequently die. To confirm that the action of KU55933 was attributable to inhibition of ATM, we show that ATM-defective cells exhibit increased sensitivity to SN38 and G2 arrest at these low concentrations, but the addition of KU55933 has no further impact. Comparison of a variety of cell lines (MDA-MB-231, MCF10A, TK-10, IGROV1) showed a 10 - 30 fold increased sensitivity to SN38 when combined with KU55933. TK-10 and IGROV1 have very low levels of the Mre11/Rad50/Nbs1(MRN) complex and do not show the G2 arrest with the combination suggesting that the MRN complex contributes to the G2 arrest but not the cytotoxicity. Sensitization by KU55933 is dependent on the type of DNA damage as inhibiting ATM did not sensitize cells to cisplatin. We propose that low levels of SN38 either transiently stall replication forks or induce a low level of DNA damage which is exacerbated by inhibition of ATM. These results suggest that in the context of combination therapy with topoisomerase I inhibitors, ATM may be a better target than Chk1.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4598.

Footnotes

  • 100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

  • American Association for Cancer Research
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Cancer Research: 69 (9 Supplement)
May 2009
Volume 69, Issue 9 Supplement
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Abstract #4598: Inhibition of ATM sensitizes cells to the topoisomerase I inhibitor SN38
Kristen Garner, Ryan Montano and Alan Eastman
Cancer Res May 1 2009 (69) (9 Supplement) 4598;

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Abstract #4598: Inhibition of ATM sensitizes cells to the topoisomerase I inhibitor SN38
Kristen Garner, Ryan Montano and Alan Eastman
Cancer Res May 1 2009 (69) (9 Supplement) 4598;
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Cancer Research Online ISSN: 1538-7445
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