Combined inhibition of topoisomerase I and poly(ADP-ribose) polymerase: A synergistic therapeutic strategy for glioblastoma with phosphatase and tensin homolog deficiency
Olga Kim, Madison Butler, Zach Sergi, Robert W. Robey, Meili Zhang, Raj Chari, Ying Pang, Guangyang Yu, Wei Zhang, Hua Song, Dionne Davis, Robert G. Hawley, Xinyu Wen, Herui Wang, Martha Quezado, Bao Tran, Mythili Merchant, Alice Ranjan, Frank B. Furnari, Javed Khan, Mark R. Gilbert, Christopher Ryan Miller, Michael M. Gottesman, Yves Pommier, Jing Wu
Abstract
Background: ) are common in glioblastoma (GBM) and have been associated with defective DNA damage repair. Here we investigated whether PTEN deficiency presents a vulnerability to a simultaneous induction of DNA damage and suppression of repair mechanisms by combining topoisomerase I (TOP1) and PARP inhibitors. Methods: Patient-derived GBM cells and isogenic PTEN-null and PTEN-WT glioma cells were treated with LMP400 (Indotecan), a novel non-camptothecin TOP1 inhibitor alone and in combination with a PARP inhibitor, Olaparib or Niraparib. RNAseq analysis was performed to identify treatment-induced dysregulated pathways. Results: We found that GBM cells lacking PTEN expression are highly sensitive to LMP400; however, rescue of the PTEN expression reduces sensitivity to the treatment. Combining LMP400 with Niraparib leads to synergistic cytotoxicity by inducing G2/M arrest, DNA damage, suppression of homologous recombination-related proteins, and activation of caspase 3/7 activity significantly more in PTEN-null cells compared to PTEN-WT cells. LMP400 and Niraparib are not affected by ABCB1 and ABCG2, the major ATP-Binding Cassette (ABC) drug efflux transporters expressed at the blood-brain barrier (BBB), thus suggesting BBB penetration which is a prerequisite for potential brain tumor treatment. Animal studies confirmed both an anti-glioma effect and sufficient BBB penetration to prolong survival of mice treated with the drug combination. Conclusions: Our findings provide a proof of concept for the combined treatment with LMP400 and Niraparib in a subset of GBM patients with PTEN deficiency.