Abstract 328: PARP inhibitors suppress growth of EGFR-mutant cancers by targeting nuclear PKM2

Abstract

Abstract Poly(ADP-robose) polymerase-1 (PARP1) or ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1) is the most abundant and the best understood member of the 17 PARP family proteins. PARP1 binds to both single strand breaks (SSBs) and double-strand breaks (DSBs) and participates in the recognition, excision and repair of DNA damage. The most extensively studied role of PARP1 is its involvement in base excision repair (BER) and PARP inhibition induced-trapping of PARP1 during BER. Moreover, suppression of PARP1/2 leads to synthetic lethality in BRCA1/2-defecient tumors, indicating that PARP1-dependent BER and BRCA-dependent homologous repair pathway have overlapping and redundant functions in DNA repair. Recent studies have also pointed to a broader utility of PARP inhibitors beyond hereditary BRCA-deficient cancers. Pyruvate kinase isoform M2 (PKM2) is a glycolysis enzyme that converts phosphoenolpyruvate (PEP) into pyruvate. Up-regulation of PKM2 has been shown recently to be an important feature of tumorigenesis. In tumor cells, PKM2 forms a dimmer that is catalytically inactive as a glycolysis enzyme, but provides advantage for tumor progression due to Warburg effect. In this report, we demonstrated that poly-ADP-ribose (PAR) is required for nuclear retention and nuclear function of PKM2. PKM2 translocates into nucleus and binds to PAR upon EGF stimulation. PARP inhibition, or the PKM2-C/A mutant, which abolishes the PKM2/PAR interaction, suppresses the nuclear function of PKM2. In addition, PARP inhibition also diminishes the nuclear PKM2-dependent glycolysis and tumor growth. Moreover, we showed that nuclear localization of PKM2 correlates with PAR expression in EGFR-mutant human lung cancer tissues. Interestingly, PARP inhibition leads to growth suppression of some EGFR-mutant lung cancer cells, which are resistant to EGFR inhibitor. These data together support an unexpected function of PARP inhibition in tumor suppression and indicate that nuclear PKM2 may serve as a promising biomarker for the further development of PARP inhibitor-based therapies. Note: This abstract was not presented at the meeting. Citation Format: Nan Li, Steven H. Lin. PARP inhibitors suppress growth of EGFR-mutant cancers by targeting nuclear PKM2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 328. doi:10.1158/1538-7445.AM2017-328