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

Ryan J Summers; Juhi Jain; Eleana Vasileiadi; Brittany Smith; Madison L Chimenti; Tsz Y Yeung; James Kelvin; Xiaodong Wang; Stephen V Frye; H Shelton Earp; Jeffrey W Tyner; Erik C Dreaden; Deborah DeRyckere; Douglas K Graham

doi:10.3390/cancers14246142

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

Cancers (Basel). 2022 Dec 13;14(24):6142. doi: 10.3390/cancers14246142.

Authors

Ryan J Summers^{1

2}, Juhi Jain³, Eleana Vasileiadi⁴, Brittany Smith⁵, Madison L Chimenti^{1

2}, Tsz Y Yeung^{1

2}, James Kelvin⁶, Xiaodong Wang⁷, Stephen V Frye⁷, H Shelton Earp⁸, Jeffrey W Tyner⁹, Erik C Dreaden^{1

2

6}, Deborah DeRyckere^{1

2}, Douglas K Graham^{1

2}

Affiliations

¹ Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, GA 30322, USA.
² Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
³ Department of Pediatrics, University of Arizona School of Medicine, Tucson, AZ 85724, USA.
⁴ Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁵ School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
⁶ Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA.
⁷ Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA.
⁸ UNC Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA.
⁹ Knight Cancer Institute, Oregon Health Sciences University, Portland, OR 97201, USA.

Abstract

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.

Keywords: BCL-2; ETP-ALL; MERTK; MRX-2843; small molecule inhibitor.

Abstract

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