Sustained NF-κB-STAT3 signaling promotes resistance to Smac mimetics in Glioma stem-like cells but creates a vulnerability to EZH2 inhibition

Cintia Carla da Hora; Kelsey Pinkham; Litia Carvalho; Max Zinter; Elie Tabet; Ichiro Nakano; Bakhos A Tannous; Christian E Badr

doi:10.1038/s41420-019-0155-9

Sustained NF-κB-STAT3 signaling promotes resistance to Smac mimetics in Glioma stem-like cells but creates a vulnerability to EZH2 inhibition

Cell Death Discov. 2019 Mar 4:5:72. doi: 10.1038/s41420-019-0155-9. eCollection 2019.

Authors

Cintia Carla da Hora^{1

2

3}, Kelsey Pinkham¹, Litia Carvalho^{1

2

3}, Max Zinter^{1

3}, Elie Tabet^{1

3}, Ichiro Nakano⁴, Bakhos A Tannous^#^{1

2

3}, Christian E Badr^#^{1

2}

Affiliations

¹ 1Department of Neurology, Massachusetts General Hospital, Boston, MA USA.
² 2Neuroscience Program, Harvard Medical School, Boston, MA USA.
³ Experimental Therapeutics and Molecular Imaging Laboratory, Charlestown, MA USA.
⁴ 4Department of Neurosurgery and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL USA.

^# Contributed equally.

Abstract

Glioblastoma is an incurable and highly aggressive brain tumor. Understanding therapeutic resistance and survival mechanisms driving this tumor type is key to finding effective therapies. Smac mimetics (SM) emerged as attractive cancer therapeutics particularly for tumor populations that are highly resistant to conventional apoptosis-inducing therapies. We evaluated the therapeutic efficacy of SM on Glioma stem-like cells (GSCs) and showed that this family of compounds stimulates an adaptive response triggered by TNFα. Increased expression of TNFα results in a prolonged and sustained activation of NF-κB and STAT3 signaling thus activating several tumor cell resistance mechanisms in GSCs. We show that STAT3 activation is contingent on EZH2 activation and uncover a synergistic lethality between SM and EZH2 inhibitors. Therapeutic inhibition of EZH2 impaired the viability of SM-treated GSCs. Our study outlines the molecular underpinnings of SM resistance in glioblastoma and provides mechanistic insight to overcome this resistance and increase therapeutic efficacy.

Abstract

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