Combined inhibition of EGFR and CK2 augments the attenuation of PI3K-Akt-mTOR signaling and the killing of cancer cells.

Abstract

Ser/Thr protein kinase CK2 regulates multiple processes that play important roles in the sensitivity of cancer to epidermal growth factor receptor targeting therapeutics, including PI3K-Akt-mTOR signaling, Hsp90 activity, and inhibition of apoptosis. We hypothesized that top-down inhibition of EGFR, combined with lateral suppression of multiple oncogenic pathways by targeting CK2, would create a pharmacologic synthetic lethal event and result in an improved cancer therapy compared to EGFR inhibition alone. This hypothesis was tested by combining CX-4945, a first-in-class clinical stage inhibitor of CK2, with the EGFR tyrosine kinase inhibitor, erlotinib, in vitro and in vivo in models of non-small cell lung carcinoma, NCI-H2170, and squamous cell carcinoma, A431. Our results demonstrate that combination of CX-4945 with erlotinib results in enhanced attenuation of the PI3K-Akt-mTOR pathway. We also observed an increase in apoptosis, synergistic killing of cancer cells in vitro, as well as improved antitumor efficacy in vivo. Taken together, these data position CK2 as a valid pharmacologic target for drug combinations and support further evaluation of CX-4945 in combination with EGFR targeting agents.

• Authors: Joshua Bliesath, Nanni Huser, Mayuko Omori, Daniel Bunag, Chris Proffitt, Nicole Streiner, Caroline Ho, Adam Siddiqui-Jain, Sean E O'Brien, John K C Lim, David M Ryckman, Kenna Anderes, William G Rice, Denis Drygin
• Journal: Cancer letters (Cancer Lett) Vol. 322 Issue 1 Pg. 113-8 (Sep 01 2012) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 22387988 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Naphthyridines
• Phenazines
• Quinazolines
• silmitasertib
• Erlotinib Hydrochloride
• MTOR protein, human
• ErbB Receptors
• Casein Kinase II
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Casein Kinase II (antagonists & inhibitors)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• ErbB Receptors (antagonists & inhibitors)
• Erlotinib Hydrochloride
• Female
• Humans
• Mice
• Naphthyridines (pharmacology)
• Neoplasms (drug therapy, pathology)
• Phenazines
• Phosphatidylinositol 3-Kinases (physiology)
• Proto-Oncogene Proteins c-akt (physiology)
• Quinazolines (pharmacology)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (physiology)