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Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90–EGFR association

Oncogene volume 35, pages 3387–3398 (2016)Cite this article

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A Corrigendum to this article was published on 20 March 2017

Abstract

Secondary mutation of epidermal growth factor receptor (EGFR) resulting in drug resistance is one of the most critical issues in lung cancer therapy. Several drugs are being developed to overcome EGFR tyrosine kinase inhibitor (TKI) resistance. Here, we report that pyruvate kinase M2 (PKM2) stabilized mutant EGFR protein by direct interaction and sustained cell survival signaling in lung cancer cells. PKM2 silencing resulted in markedly reduced mutant EGFR expression in TKI-sensitive or -resistant human lung cancer cells, and in inhibition of tumor growth in their xenografts, concomitant with downregulation of EGFR-related signaling. Mechanistically, PKM2 directly interacted with mutant EGFR and heat-shock protein 90 (HSP90), and thus stabilized EGFR by maintaining its binding with HSP90 and co-chaperones. Stabilization of EGFR relied on dimeric PKM2, and the protein half-life of mutant EGFR decreased when PKM2 was forced into its tetramer form. Clinical levels of PKM2 positively correlated with mutant EGFR expression and with patient outcome. These results reveal a previously undescribed non-glycolysis function of PKM2 in the cytoplasm, which contribute to EGFR-dependent tumorigenesis and provide a novel strategy to overcome drug resistance to EGFR TKIs.

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Acknowledgements

We thank Dr Zhimin Lu for the Flag-tagged K367M, K433E and wild-type PKM2, Dr Zhi-Ren Liu for HA-tagged R399E and wild-type PKM2, Dr Mien-Chie Hung for myc-tagged EGFR-ECM and -ICM, Dr Ann-Lii Cheng and Dr James Chih-Hsin Yang for helpful discussion, Integrated Core Facility for Functional Genomics of the National Core Facility Program for Biotechnology, the Microarray Core Facility of the National Taiwan University Center of Genomic Medicine and Dr Sung-Liang Yu for technical support. This study was supported by grants from National Science Council, Taiwan (NSC 104-2321-B-002-006, NSC-104-2911-I-002-302 and NSC 104-2923-B-002-003).

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Authors and Affiliations

  1. Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Y-C Yang

  2. Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan

    T-Y Cheng

  3. Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan

    S-M Huang, C-K Chen, K-T Hua & M-L Kuo

  4. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    C-Y Su, C-K Chen & M Hsiao

  5. Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan

    P-W Yang & J-M Lee

  6. Institute of Biochemical Sciences, College of Life Science Sciences, National Taiwan University, Taipei, Taiwan

    M-L Kuo

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Yang, YC., Cheng, TY., Huang, SM. et al. Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90–EGFR association. Oncogene 35, 3387–3398 (2016). https://doi.org/10.1038/onc.2015.397

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