EZH2i EPZ-6438 and HDACi vorinostat synergize with ONC201/TIC10 to activate integrated stress response, DR5, reduce H3K27 methylation, ClpX and promote apoptosis of multiple tumor types including DIPG

Yiqun Zhang; Lanlan Zhou; Howard Safran; Robyn Borsuk; Rishi Lulla; Nikos Tapinos; Attila A. Seyhan; Wafik S. El-Deiry

Neoplasia: An International Journal for Oncology Research (Aug 2021)

EZH2i EPZ-6438 and HDACi vorinostat synergize with ONC201/TIC10 to activate integrated stress response, DR5, reduce H3K27 methylation, ClpX and promote apoptosis of multiple tumor types including DIPG

Yiqun Zhang,
Lanlan Zhou,
Howard Safran,
Robyn Borsuk,
Rishi Lulla,
Nikos Tapinos,
Attila A. Seyhan,
Wafik S. El-Deiry

Affiliations

Yiqun Zhang: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI, USA; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA
Lanlan Zhou: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI, USA; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA
Howard Safran: The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, RI, USA
Robyn Borsuk: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Pediatric Hematology/Oncology, The Warren Alpert Medical School, Brown University, Providence, RI, USA
Rishi Lulla: The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Pediatric Hematology/Oncology, The Warren Alpert Medical School, Brown University, Providence, RI, USA
Nikos Tapinos: The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Department of Neurosurgery, The Warren Alpert Medical School, Brown University, Providence, RI, USA
Attila A. Seyhan: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI, USA; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA
Wafik S. El-Deiry: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI, USA; The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI, USA; Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA; Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, RI, USA; Corresponding author

Journal volume & issue: Vol. 23, no. 8
pp. 792 – 810

Abstract

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ONC201/TIC10 activates TRAIL signaling through ATF4 and the integrated stress response (ISR). ONC201 demonstrated tumor regressions and disease stability in patients with histone H3K27M-mutated midline-glioma. H3K27M-mutation prevents H3K27-methylation on the mutated allele. EZH2 inhibitors (EZH2i) reduce H3K27 methylation and have anti-tumor effects. We hypothesized ONC201 sensitivity and tumor apoptosis may increase by reducing H3K27-methylation with EZH2i or HDACi as mimics of H3K27M-mutation. EZH2i EPZ-6438 (tazemetostat) or PF-06821497 and HDACi vorinostat were combined with ONC201 to treat multiple cancer cell lines and cell viability and histone modifications were analyzed. We observed synergistic effects towards cell viability in multiple cancers by EPZ-6438 or PF-06821497 plus ONC201 or triple therapy with vorinostat, EPZ-6438, and ONC201. EPZ-6438 and vorinostat synergized with ONC201 to enhance apoptosis. Activation of the ISR and TRAIL-DR5 were observed in cells treated with ONC201 -/+ epigenetic modulators. Knockdown of ATF4 reduced DR5 induction and apoptosis following EZH2i and ONC201 treatment of U251 glioma cells. mRNA expression of dopamine-receptors did not correlate with ONC201 sensitivity in the tumor cell lines tested (N = 12), including changes after epigenetic drugs. Dopamine did not rescue apoptosis by ONC201 in different tumor cell lines (N = 10) including 2 GBM, 3 DIPG and did not prevent DR5 activation or apoptosis. DRD2 agonist sumanirole did not protect brain tumor cells (N = 6 including 4 DIPG cell lines) from ONC201 reduction in viability. Although synergy was observed with ONC201 and vorinostat, there was no significant increase in H3K27 acetylation in cell lines including DIPG as compared to vorinostat alone, and in some cases the acetylation was less than vorinostat alone at 72 H. H3K27 methylation reduction correlated with synergy from combinations of either EPZ-6438 or vorinostat with ONC201 or triple combination. Our findings provide a rationale for combination of ONC201 and epigenetic modulators including triple therapy for in vivo and clinical testing in treatment of human malignancies including brain tumors and DIPG.

Published in Neoplasia: An International Journal for Oncology Research

ISSN: 1522-8002 (Print); 1476-5586 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: http://www.journals.elsevier.com/neoplasia/

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