Glioblastoma (GBM) is a malignant brain cancer that is often caused by mutations that result in the increased abundance or activity of epidermal growth factor receptors (EGFRs) or other receptor tyrosine kinases or by loss of the tumor suppressor protein PTEN (phosphatase tensin homolog deleted from chromosome 10). As a result, signaling by the serine and threonine kinases phosphoinositide 3-kinase (PI3K) and its downstream effector the mammalian target of rapamycin (mTOR) are enhanced in glioblastoma cells. Noting that glioblastomas fail to respond to treatment with the mTOR inhibitor rapamycin, Iwanami et al. searched for factors that mediated this resistance. An immunohistochemical analysis of tissues from GBM patients showed that 40% of patients had an increased abundance of PML (promyelocytic leukemia), a protein that is reduced in abundance in some tumors and increased in abundance in others. Treatment of GBM cells and a GBM-derived cell line in culture with either rapamycin or the EGFR inhibitor erlotinib led to the increased abundance of PML, and overexpression studies in cultured cells showed that increased PML abundance decreased PI3K-mTOR signaling and delayed progression through the cell cycle. Knockdown of PML in GBM cell lines by small-interfering RNA (siRNA) increased the sensitivity of the cells to the induction of apoptosis by mTOR and EGFR inhibitors. Treatment of GBM cells with arsenic trioxide, a therapeutic agent that targets PML for proteasomal degradation, blocked the enhanced production of PML in response to an mTOR inhibitor and sensitized the cells to apoptosis. Finally, analysis of GBM patient tumor samples before and after treatment with rapamycin showed the increased abundance of PML after mTOR inhibition. Together, these data suggest that PML suppresses tumor cell death in response to inhibitors of mTOR and EGFR and that combined targeting of mTOR or EGFR signaling with a PML inhibitor could have therapeutic benefit.
A. Iwanami, B. Gini, C. Zanca, T. Matsutani, A. Assuncao, A. Nael, J. Dang, H. Yang, S. Zhu, J. Kohyama, I. Kitabayashi, W. K. Cavenee, T. F. Cloughesy, F. B. Furnari, M. Nakamura, Y. Toyama, H. Okano, P. S. Mischel, PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies. Proc. Natl. Acad. Sci. U.S.A. 110, 4339–4344 (2013). [Abstract] [Full]