Therapeutic Targeting of MERTK and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia.

Autor: Summers RJ; Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, GA 30322, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA., Jain J; Department of Pediatrics, University of Arizona School of Medicine, Tucson, AZ 85724, USA., Vasileiadi E; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA., Smith B; School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA., Chimenti ML; Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, GA 30322, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA., Yeung TY; Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, GA 30322, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA., Kelvin J; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA., Wang X; Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA., Frye SV; Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA., Earp HS; UNC Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA., Tyner JW; Knight Cancer Institute, Oregon Health Sciences University, Portland, OR 97201, USA., Dreaden EC; Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, GA 30322, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA., DeRyckere D; Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, GA 30322, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA., Graham DK; Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, GA 30322, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2022 Dec 13; Vol. 14 (24). Date of Electronic Publication: 2022 Dec 13.
DOI: 10.3390/cancers14246142
Abstrakt: T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of childhood ALL. The early T-precursor (ETP-ALL) subset is characterized by an immature T-cell phenotype, chemoresistance, and high rates of induction failure. MERTK receptor tyrosine kinase is ectopically expressed in half of T-ALLs, particularly those with an immature T-cell phenotype, suggesting a role in ETP-ALL. The anti-apoptotic protein B-cell lymphoma-2 (BCL-2) is essential for ETP-ALL cell survival. Here, we show that MERTK and BCL-2 mRNA and protein are preferentially expressed in ETP-ALL patient samples. The dual MERTK/FLT3 inhibitor MRX-2843 decreased MERTK activation and downstream signaling, inhibited cell expansion, and induced cell death in ETP-ALL cell lines. Further, 54% (21/39) of primary T-ALL patient samples were sensitive to MERTK inhibition. Treatment with MRX-2843 significantly reduced leukemia burden and prolonged survival in cell-line-derived T-ALL and ETP-ALL xenograft models. In a patient-derived ETP-ALL xenograft model, treatment with MRX-2843 markedly reduced peripheral blood leukemia and spleen weight compared to vehicle-treated mice and prolonged survival. MRX-2843 also synergized with venetoclax to provide enhanced anti-leukemia activity in ETP-ALL cell cultures, with a dose ratio of 1:20 MRX-2843:venetoclax providing optimal synergy. These data demonstrate the therapeutic potential of MRX-2843 in patients with T-ALL and provide rationale for clinical development. MRX-2843 monotherapy is currently being tested in patients with relapsed leukemia (NCT04872478). Further, our data indicate that combined MERTK and BCL-2 inhibition may be particularly effective for treatment of ETP-ALL.
Databáze: MEDLINE
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