Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling

Abstract

Constitutively active casein kinase 2 (CK2) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL). CK2 phosphorylates PTEN (phosphatase and tensin homolog) tumor suppressor, resulting in PTEN stabilization and functional inactivation. Downregulation of PTEN activity has an impact on PI3K/Akt/mTOR signaling, which is of fundamental importance for T-ALL cell survival. These observations lend compelling weight to the application of CK2 inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of CX-4945-a novel, highly specific, orally available, ATP-competitive inhibitor of CK2α. We show that CX-4945 treatment induced apoptosis in T-ALL cell lines and patient T lymphoblasts. CX-4945 downregulated PI3K/Akt/mTOR signaling in leukemic cells. Notably, CX-4945 affected the unfolded protein response (UPR), as demonstrated by a significant decrease in the levels of the main UPR regulator GRP78/BIP, and led to apoptosis via upregulation of the ER stress/UPR cell death mediators IRE1α and CHOP. In vivo administration of CX-4945 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth. Our findings indicate that modulation of the ER stress/UPR signaling through CK2 inhibition could be exploited for inducing apoptosis in T-ALL cells and that CX-4945 may be an efficient treatment for those T-ALLs displaying upregulation of CK2α/PI3K/Akt/mTOR signaling.

BCR-ABL inactivates cytosolic PTEN through Casein Kinase II mediated tail phosphorylation

“…45 Similar observations have been obtained in other hematological cancers, where CKII inhibitors have been associated with dramatic apoptosis induction. 36,[38][39][40][41] From a clinical perspective regarding CML therapy, we suggest that CKII inhibitors could be exploited to target imatinib resistant CML, due to BCR-ABL point mutations, and in particular by BCR-ABL-T315I. In these circumstances, CKII inhibitors promote PTEN reactivation in the presence of a sustained BCR-ABL signaling with a consequent apoptosis induction.…”

CK2 inhibitor CX-4945 destabilizes NOTCH1 and synergizes with JQ1 against human T-acute lymphoblastic leukemic cells

“…Because both JQ1 and CX-4945 exhibit anti-leukemic efficacy as single agents, 4,6 and our results show that CX-4945 destabilizes NOTCH1 and down-regulates MYC in T-ALL cells, we next asked whether CX-4945 synergizes with JQ1 to kill human T-ALL cells. To this end, we treated JURKAT, ALL-SLL, RPMI-8402 and MOLT-3 cells with serial dilutions of CX-4945 and JQ1 in combination and analyzed relative cell viability.…”

“…CK2 inhibition by CX-4945, a potent and specific inhibitor in clinical trials for treating breast cancer and multiple myeloma, significantly reduces growth and survival of human T-ALL cells, 6 and down-regulates NOTCH1 in lung cancer cells. 7 However, it remains unclear whether the cytotoxic effect of CX-4945 on T-ALL cells is associated with repression of NOTCH1 signaling.…”

“…13 Importantly, CX-4945 exhibits striking synergy with JQ1 in T-ALL cells that up-regulate CK2, cleaved-NOTCH1 and MYC. CX-4945 induces proapoptotic unfolded protein response (UPR) in T-ALL cells, 6 while JQ1 down-regulates MYC that normally activates prosurvival UPR.…”

Optimal interleukin-7 receptor-mediated signaling, cell cycle progression and viability of T-cell acute lymphoblastic leukemia cells rely on casein kinase 2 activity

“…This was demonstrated by using two distinct CK2-specific pharmacological inhibitors, TBB and CX-4945 (Silmitasertib), the latter of which has entered phase I clinical trials for refractory solid tumors and multiple myeloma, 45 and is a well-characterized, highly specific inhibitor of CK2. 35 We also tried silencing the expression of CK2a and β subunits. Notably, although we were able to efficiently knockdown CK2 in T-ALL cells by up to 80%, we only partially eliminated CK2 activity, which was sufficient to maintain normal levels of Akt S129 phosphorylation and the viability of T-ALL cells (data not shown).…”