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

Nan Li1, Lin Feng2, Hui Liu3

  • 1Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

Cell Reports
|May 7, 2016
PubMed

Insights

Poly(ADP-ribose) (PAR) binding anchors nuclear pyruvate kinase M2 (PKM2), driving cancer growth. PARP inhibitors block this, suppressing tumor progression and offering a new strategy for EGFR-inhibitor-resistant lung cancers.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Pyruvate kinase M2 (PKM2) translocates to the nucleus upon growth factor stimulation or in EGFR-mutant cancers, promoting glycolysis and cell growth.
  • Nuclear PKM2 function is crucial for cancer cell proliferation and tumor development.

Purpose of the Study:

  • To investigate the role of poly-ADP-ribose (PAR) in PKM2 nuclear localization.
  • To explore the therapeutic potential of targeting PAR-dependent PKM2 nuclear function in EGFR-mutant cancers.

Main Methods:

  • Investigated the direct binding of PKM2 to poly-ADP-ribose (PAR).
  • Assessed the effect of PARP inhibition on PKM2 nuclear localization, cell proliferation, and tumor growth.
  • Correlated PAR levels with PKM2 nuclear localization in EGFR-mutant brain and lung cancers.

Main Results:

  • Nuclear PKM2 directly binds to PAR, which is essential for its nuclear localization.
  • PARP inhibition prevents PKM2 nuclear retention, suppressing cancer cell proliferation and tumor growth.
  • PAR levels correlate with nuclear PKM2 localization in EGFR-mutant glioblastoma and lung cancers, indicating a role in tumor progression.

Conclusions:

  • PAR-dependent nuclear localization of PKM2 contributes to tumor progression in EGFR-mutant cancers.
  • PARP inhibitors suppress PKM2 nuclear function, representing a viable treatment strategy for EGFR-inhibitor-resistant lung cancers.

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