Effect of CX-4945, a selective bioavailable small molecule inhibitor of protein kinase CK2, on gemcitabine antitumor activity in A2780 ovarian cancer.

Abstract

e13522 Background: The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Resistance occurs against every effective anticancer drug and can develop by numerous mechanisms including activation of DNA repair mechanisms. X-ray repair cross-complementing protein 1 (XRCC1) is one of the most important DNA repair genes and is required for efficient single strand break/base excision repair. XRCC1 is positively regulated by CK2, a highly conserved, constitutively active serine/threonine protein kinase that is implicated in critical cellular processes and is a key participant in the cellular response to DNA damage. CK2 activity and expression levels are elevated in many cancers of diverse genetic background and have been linked to disease progression and poor prognosis. CK2 overexpression may enhance DNA repair in cancer cells via activation of XRCC1 thereby mediating MDR. CX-4945 is a potent, selective small molecule inhibitor of CK2 with single agent activity in xenografts. Methods: We investigated the role of CK2 in DNA repair using CX-4945 in combination with gemcitabine in the A2780 model of ovarian cancer. Effects on cell cycle, cell viability, molecular markers and antitumor activity were assessed. Results: CX-4945 effectively abrogated gemcitabine-induced S-phase cell cycle arrest and resulted in synergistic killing of A2780 cells. CX-4945 inhibited phosphorylation of XRCC1 at CK2 specific phosphorylation sites (Thr488, Ser518, and Thr519/523). In A2780 xenografts combination gemcitabine + CX-4945 was well tolerated and showed significant delay in time to endpoint of 11 days and 6/10 regressions versus no regressions with gemcitabine alone. Conclusions: Inhibition of CK2 by CX-4945 enhances the antitumor activity of gemcitabine via disruption of cell cycle checkpoints and DNA repair signaling triggered by gemcitabine-induced DNA damage. CK2 inhibitors represent an important element of combination chemotherapy strategy due to the roles of CK2 in DNA repair and chemoresistance. A phase I clinical trial of CX-4945 in patients with advanced solid tumors or multiple myeloma is currently in progress. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cylene Pharmaceuticals Cylene Pharmaceuticals