Reference Detail

Ref Type Journal Article
PMID (28151717)
Authors Pikman Y, Alexe G, Roti G, Conway AS, Furman A, Lee ES, Place AE, Kim S, Saran C, Modiste R, Weinstock DM, Harris M, Kung AL, Silverman LB, Stegmaier K
Title Synergistic Drug Combinations with a CDK4/6 Inhibitor in T-cell Acute Lymphoblastic Leukemia.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 23
Issue 4
Date 2017 Feb 15
URL
Abstract Text Purpose: Although 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 wild-type T-ALL are highly sensitive to pharmacologic inhibition of CDK4/6 when wild-type 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, an mTOR inhibitor, and gamma secretase inhibitor. 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.Conclusions: We conclude that LEE011 is active in T-ALL and that combination therapy with corticosteroids and/or mTOR inhibitors warrants further investigation. Clin Cancer Res; 23(4); 1012-24. ©2016 AACRSee related commentary by Carroll et al., p. 873.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NOTCH1 wild-type RB1 wild-type T-cell adult acute lymphocytic leukemia decreased response Mercaptopurine + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the addition of Kisqali (ribociclib) to Purixan (mercaptopurine) resulted in an antagonistic effect in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and wild-type NOTCH1 in culture (PMID: 28151717). 28151717
NOTCH1 mut RB1 wild-type T-cell adult acute lymphocytic leukemia decreased response Mercaptopurine + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the addition of Kisqali (ribociclib) to Purixan (mercaptopurine) resulted in an antagonistic effect in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and a NOTCH1 mutation in culture (PMID: 28151717). 28151717
NOTCH1 mut RB1 wild-type T-cell adult acute lymphocytic leukemia sensitive Dexamethasone + Ribociclib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Kisqali (ribociclib) and Adexone (dexamethasone) treatment in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and a NOTCH1 mutation resulted in decreased cell viability and reduced phosphorylation of Rb1 in culture, and a greater survival benefit in xenograft models when compared to Kisqali (ribociclib) alone (PMID: 28151717). 28151717
NOTCH1 wild-type RB1 wild-type T-cell adult acute lymphocytic leukemia sensitive Bortezomib + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the combination of Kisqali (ribociclib) and Velcade (bortezomib) resulted in an additive effect in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and wild-type NOTCH1 in culture (PMID: 28151717). 28151717
NOTCH1 wild-type RB1 wild-type T-cell adult acute lymphocytic leukemia sensitive Everolimus + Ribociclib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Kisqali (ribociclib) and Afinitor (everolimus) treatment in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and wild-type NOTCH1 resulted in decreased Rb1 phosphorylation and a greater inhibition of cell growth compared to either agent alone in culture, and prolonged survival in cell-line xenograft models (PMID: 28151717). 28151717
NOTCH1 wild-type RB1 wild-type T-cell adult acute lymphocytic leukemia sensitive Prednisolone + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the combination of Kisqali (ribociclib) and Omnipred (prednisolone) resulted in a synergistic effect in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and wild-type NOTCH1 in culture (PMID: 28151717). 28151717
NOTCH1 mut RB1 wild-type T-cell adult acute lymphocytic leukemia sensitive Prednisolone + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the combination of Kisqali (ribociclib) and Omnipred (prednisolone) resulted in a synergistic effect in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and a NOTCH1 mutation in culture (PMID: 28151717). 28151717
NOTCH1 mut RB1 wild-type T-cell adult acute lymphocytic leukemia sensitive Everolimus + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the combination of Kisqali (ribociclib) and Afinitor (everolimus) treatment in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and a NOTCH1 mutation resulted in decreased Rb1 phosphorylation and a greater inhibition of cell growth compared to either agent alone in culture (PMID: 28151717). 28151717
NOTCH1 mut RB1 wild-type T-cell adult acute lymphocytic leukemia sensitive Bortezomib + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the combination of Kisqali (ribociclib) and Velcade (bortezomib) resulted in an additive effect in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and a NOTCH1 mutation in culture (PMID: 28151717). 28151717
NOTCH1 mut RB1 wild-type T-cell adult acute lymphocytic leukemia decreased response Asparaginase + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the addition of Kisqali (ribociclib) to Elspar (asparaginase) resulted in an antagonistic effect in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and a NOTCH1 mutation in culture (PMID: 28151717). 28151717
NOTCH1 mut RB1 wild-type T-cell adult acute lymphocytic leukemia decreased response Methotrexate + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the addition of Kisqali (ribociclib) to Methotrexate resulted in an antagonistic effect in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and a NOTCH1 mutation in culture (PMID: 28151717). 28151717
NOTCH1 act mut T-cell adult acute lymphocytic leukemia predicted - sensitive Dexamethasone + Ribociclib Preclinical - Pdx Actionable In a preclinical study, the combination of Kisqali (ribociclib) and Adexone (dexamethasone) resulted in reduced leukemia burden and a greater survival benefit in a NOTCH1 activated T-cell acute lymphoblastic leukemia patient derived xenograft (PDX) model when compared to control or either agent alone (PMID: 28151717). 28151717
NOTCH1 wild-type RB1 loss T-cell adult acute lymphocytic leukemia resistant Ribociclib Preclinical - Cell culture Actionable In a preclinical study, a T-cell acute lymphoblastic leukemia cell line harboring wild-type NOTCH1 and loss of RB1 demonstrated resistance to Kisqali (ribociclib) in culture, resulting in limited inhibition of cell growth (PMID: 28151717). 28151717
NOTCH1 wild-type RB1 wild-type T-cell adult acute lymphocytic leukemia conflicting Dexamethasone + Ribociclib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Kisqali (ribociclib) and Adexone (dexamethasone) in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and NOTCH1 resulted in decreased cell viability and reduced phosphorylation of Rb1 in culture, however, survival did not differ between xenograft models treated with the combination or Kisqali (ribociclib) alone (PMID: 28151717). 28151717
NOTCH1 wild-type RB1 wild-type T-cell adult acute lymphocytic leukemia sensitive JQ1 + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the combination of Kisqali (ribociclib) and JQ1 resulted in an additive effect in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and wild-type NOTCH1 in culture (PMID: 28151717). 28151717
NOTCH1 wild-type RB1 wild-type T-cell adult acute lymphocytic leukemia sensitive Ribociclib Preclinical - Cell culture Actionable In a preclinical study, a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and wild-type NOTCH1 demonstrated sensitivity to treatment with Kisqali (ribociclib) in culture, resulting in inhibition of cell growth (PMID: 28151717). 28151717
NOTCH1 mut RB1 wild-type T-cell adult acute lymphocytic leukemia sensitive Ribociclib Preclinical - Cell culture Actionable In a preclinical study, a T-cell acute lymphoblastic leukemia cell line co-harboring wild-type RB1 and a NOTCH1 mutation demonstrated sensitivity to treatment with Kisqali (ribociclib) in culture, resulting in inhibition of cell growth (PMID: 28151717). 28151717
NOTCH1 mut RB1 wild-type T-cell adult acute lymphocytic leukemia sensitive JQ1 + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the combination of Kisqali (ribociclib) and JQ1 resulted in an additive effect in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and a NOTCH1 mutation in culture (PMID: 28151717). 28151717
NOTCH1 wild-type RB1 wild-type T-cell adult acute lymphocytic leukemia decreased response Methotrexate + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the addition of Kisqali (ribociclib) to Methotrexate resulted in an antagonistic effect in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and wild-type NOTCH1 in culture (PMID: 28151717). 28151717
NOTCH1 wild-type RB1 wild-type T-cell adult acute lymphocytic leukemia decreased response Asparaginase + Ribociclib Preclinical - Cell culture Actionable In a preclinical study, the addition of Kisqali (ribociclib) to Elspar (asparaginase) resulted in an antagonistic effect in a T-cell acute lymphoblastic leukemia cell line harboring wild-type RB1 and wild-type NOTCH1 in culture (PMID: 28151717). 28151717