PARP Inhibition Suppresses Growth of EGFR-Mutant Cancers by Targeting Nuclear PKM2

•Nuclear PKM2 binds to poly-ADP-ribose•PAR binding is required for PKM2 nuclear retention•PARP inhibition suppresses growth of EGFR mutant cancers•PAR level correlates with nuclear localization of PKM2 in EGFR mutant cancers

SummaryUpon 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.

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