EGFR Signals to mTOR Through PKC and Independently of Akt in Glioma

Qi-Wen Fan^1,2,3,4, Christine Cheng^1,2,3,4, Zachary A. Knight^5,6,7, Daphne Haas-Kogan^3,4, David Stokoe^3,4, C. David James^3,4, Frank McCormick⁴, Kevan M. Shokat^5,6,7, and William A. Weiss^1,2,3,4,5*

¹ Department of Neurology, University of California, 533 Parnassus Avenue, San Francisco, CA 94143, USA.
² Department of Pediatrics, University of California, San Francisco, CA 94143, USA.
³ Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, CA 94143, USA.
⁴ Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
⁵ Program in Chemistry and Chemical Biology, University of California, San Francisco, CA 94158, USA.
⁶ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
⁷ Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA.

Abstract: Amplification of the gene encoding the epidermal growth factor (EGF) receptor (EGFR) occurs commonly in glioblastoma, leading to activation of downstream kinases including phosphatidylinositol 3'-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). Here, we show that phosphorylation of mTOR and its downstream substrate rpS6 (ribosomal protein S6) are robust biomarkers for the antiproliferative effect of EGFR inhibitors. Inhibition of EGFR signaling correlated with decreased abundance of phosphorylated mTOR (p-mTOR) and rpS6 (p-rpS6) in cells wild type for the gene encoding PTEN (phosphatase and tensin homolog on chromosome 10), a negative regulator of PI3K. In contrast, inhibition of EGFR signaling failed to affect p-mTOR or p-rpS6 in cells mutant for PTEN, which are resistant to EGFR inhibitors. Although the abundance of phosphorylated Akt (p-Akt) decreased in response to inhibition of EGFR signaling, Akt was dispensable for signaling between EGFR and mTOR. We identified an Akt-independent pathway linking EGFR to mTOR that was critically dependent on protein kinase C (PKC). Consistent with these observations, the abundance of EGFR generally correlated with phosphorylation of rpS6 and PKC in primary human glioblastoma tumors, and correlated poorly with phosphorylation of Akt. Inhibition of PKC led to decreased viability of glioma cells regardless of PTEN or EGFR status, suggesting that PKC inhibitors should be tested in glioma. These findings underline the importance of signaling between EGFR and mTOR in glioma, identify PKC as essential to this network, and question the necessity of Akt as a critical intermediate coupling EGFR and mTOR in glioma.

* To whom correspondence should be addressed. E-mail: weiss{at}cgl.ucsf.edu

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