PLK1 inhibition enhances temozolomide efficacy in IDH1 mutant gliomas.
Despite multimodal therapy with radiation and the DNA alkylating agent temozolomide (TMZ), malignant gliomas remain incurable. Up to 90% of grades II-III gliomas contain a single mutant isocitrate dehydrogenase 1 (IDH1) allele. IDH1 mutant-mediated transformation is associated with TMZ resistance; however, there is no clinically available means of sensitizing IDH1 mutant tumors to TMZ. In this study we sought to identify a targetable mechanism of TMZ resistance in IDH1 mutant tumors to enhance TMZ efficacy. IDH1 mutant astrocytes rapidly bypassed the G2 checkpoint with unrepaired DNA damage following TMZ treatment. Checkpoint adaptation was accompanied by PLK1 activation and IDH1 mutant astrocytes were more sensitive to treatment with BI2536 and TMZ in combination (<20% clonogenic survival) than either TMZ (~60%) or BI2536 (~75%) as single agents. In vivo, TMZ or BI2536 alone had little effect on tumor size. Combination treatment caused marked tumor shrinkage in all mice and complete tumor regression in 5 of 8 mice. Mutant IDH1 promotes checkpoint adaptation which can be exploited therapeutically with the combination of TMZ and a PLK1 inhibitor, indicating PLK1 inhibitors may be clinically valuable in the treatment of IDH1 mutant gliomas.
Department of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati, Cincinnati, OH, USA.
Robert F
RF
Koncar
Department of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati, Cincinnati, OH, USA.
Zhengtao
Z
Chu
Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Lindsey E
LE
Romick-Rosendale
Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Susanne I
SI
Wells
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Timothy A
TA
Chan
Department of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati, Cincinnati, OH, USA.
Xiaoyang
X
Qi
Department of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati, Cincinnati, OH, USA.
El Mustapha
EM
Bahassi
D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000378:metabolism*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D000077204:Temozolomide; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D003606:Dacarbazine; D007521:Isocitrate Dehydrogenase; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000077204:Temozolomide; D000097869:Polo-Like Kinase 1
IDH1; PLK1; checkpoint adaptation; glioma; temozolomide