Synergistic Drug Combinations with a CDK4/6 Inhibitor in T-cell Acute Lymphoblastic Leukemia

Abstract

Purpose While significant progress has been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), many patients will require additional therapy for relapsed/refractory disease. Cyclin D3 (CCND3) and CDK6 are highly expressed in T-ALL and have been effectively targeted in mutant NOTCH1-driven mouse models of this disease with a CDK4/6 small-molecule inhibitor. Combination therapy, however, will be needed for the successful treatment of human disease. Experimental Design We performed preclinical drug testing using a panel of T-ALL cell lines first with LEE011, a CDK4/6 inhibitor, and next with the combination of LEE011 with a panel of drugs relevant to T-ALL treatment. We then tested the combination of LEE011 with dexamethasone or everolimus in three orthotopic mouse models and measured on-target drug activity. Results We first determined that both NOTCH1 mutant and wildtype T-ALL are highly sensitive to pharmacological inhibition of CDK4/6 when wildtype RB is expressed. Next, we determined that CDK4/6 inhibitors are antagonistic when used either concurrently or in sequence with many of the drugs used to treat relapsed T-ALL (methotrexate, mercaptopurine, asparaginase and doxorubicin) but are synergistic with glucocorticoids, mTOR inhibitor, and gamma secretase inhibitor (GSI). The combinations of LEE011 with the glucocorticoid dexamethasone or the mTOR inhibitor everolimus were tested in vivo and prolonged survival in three orthotopic mouse models of T-ALL. On-target activity was measured in peripheral blood and tissue of treated mice. Conclusion We conclude that LEE011 is active in T-ALL and that combination therapy with corticosteroids and/or mTOR inhibitors warrants further investigation.

Phase I trial of the mTOR inhibitor everolimus in combination with multi‐agent chemotherapy in relapsed childhood acute lymphoblastic leukemia

“…The combination of everolimus and chemotherapy should also be explored more thoroughly in the relapsed T‐ALL setting, given that these patients have a dismal prognosis and are currently unable to benefit from the novel immunotherapeutic approaches that primarily target B ALL‐specific antigens. In addition to administering everolimus with standard cytotoxic chemotherapy, preclinical data suggest that combining it with other targeted agents, such as CDK 4/6 and gamma‐secretase inhibitors, may be especially beneficial in T‐ALL and in patients with B‐ALL with very high‐risk features . Finally, incorporation of everolimus into upfront treatment regimens for newly diagnosed patients with adverse presenting characteristics and/or poor early response should be considered as a mechanism to prevent chemoresistance and ultimately reduce the incidence of relapse.…”

“…In addition to administering everolimus with standard cytotoxic chemotherapy, preclinical data suggest that combining it with other targeted agents, such as CDK 4/6 and gammasecretase inhibitors, may be especially beneficial in T-ALL and in patients with B-ALL with very high-risk features. 7,9,[37][38][39][40] Finally, incorporation of everolimus into upfront treatment regimens for newly diagnosed patients with adverse presenting characteristics and/or poor early response should be considered as a mechanism to prevent chemoresistance and ultimately reduce the incidence of relapse.…”

Can one target T-cell ALL?

“…Importantly, loss of the retinoblastoma tumor suppressor gene can be recurrently found in adult T-ALL [28] and loss of RB can abrogate the antitumor effects of CDK4/CDK6 inhibitors. In addition, it should be noted that CDK4/CDK6 inhibition can have an antagonistic effect with chemotherapy agents with cycle dependent activity as a result of decreased cell proliferation [29]. …”

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

“…Importantly, observations of dose-dependent decreases in phosphorylated Rb and FOXM1, highlight cellular senescence could be an important mechanism associated with the clinical activity of this agent. Ribociclib was active in vitro in leukemia cells (17) and in vivo in mutant NOTCH1-driven T-ALL mouse models in combination therapy with corticosteroids and mTOR inhibitors (18). Dual inhibition of MEK1/2 (binimetinib) and CDK4/6 (ribociclib) achieved preclinical synergy (19), as well as ALK (ceritinib) and CDK4/6 (ribociclib) (20) in neuroblastoma.…”