Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC201 in solid tumors

• Published in: PloS one Vol. 12; no. 8; p. e0180541
• Main Authors: Prabhu, Varun V, Lulla, Amriti R, Madhukar, Neel S, Ralff, Marie D, Zhao, Dan, Kline, Christina Leah B, Van den Heuvel, A Pieter J, Lev, Avital, Garnett, Mathew J, McDermott, Ultan, Benes, Cyril H, Batchelor, Tracy T, Chi, Andrew S, Elemento, Olivier, Allen, Joshua E, El-Deiry, Wafik S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.08.2017; Public Library of Science (PLoS)
• Subjects: AKT protein; Analysis; Antineoplastic Agents - pharmacology; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological markers; Biology and Life Sciences; Biomarkers; Biomarkers, Tumor - genetics; Biotechnology; Brain cancer; Cancer; Cancer cells; Cancer genetics; Cancer therapies; CD44 antigen; Cell death; Cell Line, Tumor; Cell self-renewal; Cell survival; Cell Survival - drug effects; Central Nervous System Neoplasms - genetics; Central Nervous System Neoplasms - physiopathology; Chemotherapy; Clinical trials; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - physiopathology; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genes; Glioblastoma; Glioblastoma - genetics; Glioblastoma - physiopathology; Glioblastoma cells; HCT116 Cells; Health aspects; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humans; Hyaluronan Receptors - genetics; Hyaluronan Receptors - metabolism; Id1 protein; Imidazoles; Inhibition; Inhibitor of Differentiation Protein 1 - genetics; Inhibitor of Differentiation Protein 1 - metabolism; Kinases; Medical research; Medical schools; Medicine; Medicine and Health Sciences; Metastases; Metastasis; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Network analysis; Pharmacodynamics; Pharmacology; Predictions; Prostate cancer; Pyridines; Pyrimidines; Ribonucleic acid; RNA; Solid tumors; Stem cells; Stress response; Studies; TRAIL protein; Transcriptome; Tumor cell lines; Tumors; Wnt protein; Wnt Signaling Pathway - drug effects; United States > US; Massachusetts; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0180541

Cancer stem cells (CSCs) correlate with recurrence, metastasis and poor survival in clinical studies. Encouraging results from clinical trials of CSC inhibitors have further validated CSCs as therapeutic targets. ONC201 is a first-in-class small molecule imipridone in Phase I/II clinical trials for advanced cancer. We have previously shown that ONC201 targets self-renewing, chemotherapy-resistant colorectal CSCs via Akt/ERK inhibition and DR5/TRAIL induction. In this study, we demonstrate that the anti-CSC effects of ONC201 involve early changes in stem cell-related gene expression prior to tumor cell death induction. A targeted network analysis of gene expression profiles in colorectal cancer cells revealed that ONC201 downregulates stem cell pathways such as Wnt signaling and modulates genes (ID1, ID2, ID3 and ALDH7A1) known to regulate self-renewal in colorectal, prostate cancer and glioblastoma. ONC201-mediated changes in CSC-related gene expression were validated at the RNA and protein level for each tumor type. Accordingly, we observed inhibition of self-renewal and CSC markers in prostate cancer cell lines and patient-derived glioblastoma cells upon ONC201 treatment. Interestingly, ONC201-mediated CSC depletion does not occur in colorectal cancer cells with acquired resistance to ONC201. Finally, we observed that basal expression of CSC-related genes (ID1, CD44, HES7 and TCF3) significantly correlate with ONC201 efficacy in >1000 cancer cell lines and combining the expression of multiple genes leads to a stronger overall prediction. These proof-of-concept studies provide a rationale for testing CSC expression at the RNA and protein level as a predictive and pharmacodynamic biomarker of ONC201 response in ongoing clinical studies.