Upregulation of nuclear PML in glioblastoma confers resistance to mTOR-targeted therapies.

  • Major finding: Upregulation of nuclear PML in glioblastoma confers resistance to mTOR-targeted therapies.

  • Mechanism: mTOR and EGFR inhibitors induce PML expression, which blocks drug-induced cancer cell death.

  • Impact: Addition of low-dose arsenic trioxide enhances sensitivity to mTOR kinase inhibition in mice.

Activation of the phosphoinositide 3-kinase (PI3K)/mTOR pathway is common in glioblastoma multiforme (GBM) tumors, prompting investigation of mTOR inhibitors for the treatment of this disease. However, clinical trials using rapamycin have been unsuccessful, as GBM tumors develop resistance to these inhibitors, in part through relief of negative feedback and activation of AKT signaling. Iwanami and colleagues hypothesized that the promyelocytic leukemia (PML) protein, which negatively regulates PI3K/mTOR activity and has been implicated in drug resistance in leukemia, may function as an additional mechanism of mTOR inhibitor resistance in GBM. Inhibition of mTOR signaling via treatment with rapamycin, the dual mTOR complex 1 (mTORC1) and mTORC2 kinase inhibitor pp242, or the EGF receptor (EGFR) kinase inhibitor erlotinib resulted in increased nuclear expression of PML in GBM cell lines, patient-derived cancer cells, and tumor biopsy tissue. PML overexpression suppressed PI3K/AKT/mTOR signaling and slowed cell-cycle progression, consistent with the finding that PML expression in GBM tumors was inversely correlated with markers of proliferation and mTORC1 activation. PML overexpression also reduced the growth-inhibitory effect of rapamycin treatment, whereas knockdown of PML enhanced the sensitivity of GBM cell lines to pp242- and erlotinib-stimulated cell death, suggesting that PML confers mTOR and EGFR inhibitor resistance. Furthermore, combined treatment with pp242 and low-dose arsenic trioxide, which is used to treat promyelocytic leukemia and targets PML for degradation, prevented pp242-driven PML upregulation and promoted GBM cell death in the absence of p53 activation; arsenic trioxide also synergized with pp242 in vivo, resulting in augmented cancer cell apoptosis and diminished xenograft tumor growth. Although additional work is needed to determine whether PML mediates resistance by inducing a quiescent cell state, these results suggest a combinatorial therapeutic strategy that may overcome mTOR inhibitor resistance in patients with GBM.

Iwanami A, Gini B, Zanca C, Matsutani T, Assuncao A, Nael A, et al. PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies. Proc Natl Acad Sci U S A 2013 Feb 25 [Epub ahead of print].