Inhibition of calcineurin combined with dasatinib has direct and indirect anti‐leukemia effects against BCR‐ABL1⁺ leukemia

Abstract

Treatment of BCR-ABL1+ leukemia has been revolutionized with the development of tyrosine kinase inhibitors. However, patients with BCR-ABL1+ acute lymphoblastic leukemia and subsets of patients with chronic myeloid leukemia are at high risk of relapse despite kinase inhibition therapy, necessitating novel treatment strategies. We previously reported synthetic lethality in BCR-ABL1+ leukemia cells by blocking both calcineurin/NFAT signaling and BCR-ABL1, independent of drug efflux inhibition by cyclosporine. Here, using RNA-interference we confirm that calcineurin inhibition sensitizes BCR-ABL1+ cells to tyrosine kinase inhibition in vitro. However, when we performed pharmacokinetic and pharmacodynamic studies of dasatinib and cyclosporine in mice, we found that co-administration of cyclosporine increases peak concentrations and the area under the curve of dasatinib, which contributes to the enhanced disease control. We also report the clinical experience of two subjects in whom we observed more hematopoietic toxicity than expected while enrolled in a Phase Ib trial designed to assess the safety and tolerability of adding cyclosporine to dasatinib in humans. Thus, the anti-leukemia benefit of co-administration of cyclosporine and dasatinib is mechanistically pleiotropic, but may not be tolerable, at least as administered in this trial. These data highlight some of the challenges associated with combining targeted agents to treat leukemia.

Deregulation of calcium homeostasis in Bcr-Abl-dependent chronic myeloid leukemia

“…A clinical trial showed that a combination of NFAT inhibitor cyclosporine with dasatinib facilitated leukemia cells elimination and improved survival of Bcr-Abl acute lymphoblastic leukemia [ 84 ]. Nevertheless, the phase 1b of this clinical trial concluded that this combined treatment may not be well tolerated [ 85 ]. Although, a recent proteomic analysis revealed that Ca 2+ homeostasis actors could be good targets in TKI-resistant CML [ 86 ].…”

IL12 Abrogates Calcineurin-Dependent Immune Evasion during Leukemia Progression

“…[20][21][22][23]. Leukemia cells were transduced with lentiviruses expressing nonsilencing control shRNA (shNS) or shRNA against Ppp3r1, which encodes the essential regulatory subunit of calcineurin (shCnB), with over 90% knockdown as described previously (14). A total of 5 Â 10 5 cells were transferred via tail vein injection into unirradiated, 6-to 8-week-old, female wild-type (WT) or immune-compromised recipients.…”

“…Although calcineurin's function is best defined in T cells, it has also been studied for its role in oncogenesis and drug resistance in leukemia and lymphoma. For example, BCR-ABL1 þ leukemia cells become dependent upon calcineurin when exposed to tyrosine kinase inhibition (13,14). In addition, calcineurin and one of its downstream substrates, NFAT, are activated in lymphoma and leukemia, suggesting a role in pathogenesis (15,16).…”

“…While investigating the role of leukemia-cell calcineurin in resistance to tyrosine kinase inhibition (13,14), we made the striking observation that calcineurin-deficient leukemia cells engraft and progress in immune-competent recipients, but later regress to below the level of detection, resulting in long-term survival. This is in stark contrast to the Cn-expressing leukemia, which rapidly and uniformly progresses to fatal disease within 14-21 days.…”

The role of dasatinib in the management of chronic myeloid leukemia

“…Resistance to imatinib led to the development of novel TKIs. 10 , 11 Dasatinib (Sprycel ® , Bristol-Myers Squibb, New York, NY, USA), a second-generation TKI, was approved by the US Food and Drug Administration (FDA) in 2010 at 100 mg once daily as the starting dose in patients with chronic phase CML and at 70 mg twice daily in patients for the treatment of chronic, blastic, or accelerated phase CML resistant or intolerant to previous treatment, including imatinib. 11 – 13 Various clinical trials have provided evidence that it has more durable complete hematologic and cytogenetic responses and more potency (325 times more active) compared to imatinib.…”