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

• Published in: Blood 2015-12, Vol.126 (23), p.2488-2488
• Main Authors: Pikman, Yana, Furman, Andrew, Lee, Emily S., Place, Andrew E., Alexe, Gabriela, Modiste, Rebecca, Gokhale, Prafulla, Kim, Sunkyu, Silverman, Lewis B., Stegmaier, Kimberly
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V126.23.2488.2488

While significant progress has been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), approximately 10-20% of newly diagnosed patients will experience either induction failure or relapse. Additionally, fewer than 50% of T-ALL patients who experience a relapse are long-term survivors. New targeted therapies are needed for the treatment of this disease. Multiple lines of evidence point to Cyclin D3/CDK4/6 as a potential therapeutic target in T-ALL. Cyclin D3 (CCND3), a direct target of activated NOTCH1, is upregulated in T-ALL, and CCND3 null animals are refractory to NOTCH1 driven T-ALL. CCND3 binds and activates CDK4/6, and the CCND3-CDK complex phosphorylates the tumor suppressor RB leading to cell cycle progression. Previous studies have demonstrated that CDK4/6 small-molecule inhibition is an effective therapeutic strategy for the treatment of NOTCH1-driven T-ALL mouse models. Using the publicly available Genomics of Drug Sensitivity in Cancer data set, we identified NOTCH1 mutations as a biomarker of response and RB mutations as a biomarker of resistance to the CDK4/6 inhibitor palbociclib. We validated that RB null status predicts resistance to the Novartis CDK4/6 inhibitor LEE011 in a panel of T-ALL cell lines. Interestingly, we identified both NOTCH1 mutant, as well as NOTCH1 wildtype, T-ALL cell lines that were sensitive to LEE011 treatment. Mining of publicly available data revealed that CDK6 is consistently marked by a super-enhancer in T-ALL cell lines, both NOTCH1 mutant and wildtype, suggesting another potential reason for sensitivity to CDK4/6 inhibition in this lineage. Treatment with LEE011 also led to a dose-dependent cell cycle arrest and cell death in T-ALL cells, including MOLT4 (NOTCH1 mutant) and MOLT16 (NOTCH1 wildtype). Combinations of drugs with CDK4/6 inhibitors will likely be critical for the successful translation of this drug class because they generally do not induce cell death. Combinations with cytotoxic chemotherapy are predicted to be antagonistic, however, as most of these drugs rely on rapidly proliferating cells, and CDK4/6 inhibition induces cell cycle arrest. To discover effective, and immediately translatable combination therapies with LEE011 in T-ALL, we performed combination studies of LEE011 with agents standardly used for T-ALL treatment, including corticosteroids, methotrexate, mercaptopurine, asparaginase, vincristine and doxorubicin. Combinations of LEE011 with methotrexate, mercaptopurine,