title: PARP Inhibition Suppresses Growth of EGFR-Mutant Cancers by Targeting Nuclear PKM2.
abstract: Upon growth factor stimulation or in some EGFR mutant cancer cells, PKM2 translocates into the nucleus to induce glycolysis and cell growth. Here, we report that nuclear PKM2 binds directly to poly-ADP ribose, and this PAR-binding capability is critical for its nuclear localization. Accordingly, PARP inhibition prevents nuclear retention of PKM2 and therefore suppresses cell proliferation and tumor growth. In addition, we found that PAR level correlates with nuclear localization of PKM2 in EGFR mutant brain and lung cancers, suggesting that PAR-dependent nuclear localization of PKM2 likely contributes to tumor progression in EGFR mutant glioblastoma and lung cancers. In addition, some EGFR-inhibitor-resistant lung cancer cells are sensitive to PARP inhibitors. Taken together, our data indicate that suppression of PKM2 nuclear function by PARP inhibitors represents a treatment strategy for EGFR-inhibitor-resistant cancers.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Sun Yat-sen University Cancer Center and State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Institute of System Biomedicine and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
authors.forename: Jiadong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Moses
authors.initials: M
authors.lastname: Kasembeli
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: My Kim
authors.initials: MK
authors.lastname: Tran
authors.affiliation: Division of Internal Medicine, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tweardy
authors.affiliation: Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Steven Hsesheng
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: jchen8@mdanderson.org.
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen