RBL2 Regulates Cardiac Sensitivity to Anthracycline Chemotherapy

Peng Xia; Jingrui Chen; Yadav Sapkota; Erika N Scott; Yuening Liu; Melissa M Hudson; Shahrad R Rassekh; Bruce C Carleton; Colin J D Ross; Eric J Chow; Zhaokang Cheng

doi:10.1016/j.jaccao.2022.10.017

RBL2 Regulates Cardiac Sensitivity to Anthracycline Chemotherapy

JACC CardioOncol. 2023 Mar 28;5(3):360-373. doi: 10.1016/j.jaccao.2022.10.017. eCollection 2023 Jun.

Authors

Peng Xia¹, Jingrui Chen¹, Yadav Sapkota², Erika N Scott^{3

4}, Yuening Liu¹, Melissa M Hudson^{2

5}, Shahrad R Rassekh^{4

6}, Bruce C Carleton^{4

7

8}, Colin J D Ross^{3

4

9}, Eric J Chow¹⁰, Zhaokang Cheng¹

Affiliations

¹ Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington, USA.
² Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
³ Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
⁴ British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
⁵ Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
⁶ Division of Pediatric Hematology/Oncology/Bone Marrow Transplantation, Department of Pediatrics, British Columbia Children's Hospital and Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
⁷ Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
⁸ Pharmaceutical Outcomes Programme, British Columbia Children's Hospital, Vancouver, British Columbia, Canada.
⁹ Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁰ Fred Hutchinson Cancer Center, Seattle, Washington, USA.

Abstract

Background: Anthracycline chemotherapies cause heart failure in a subset of cancer patients. We previously reported that the anthracycline doxorubicin (DOX) induces cardiotoxicity through the activation of cyclin-dependent kinase 2 (CDK2).

Objectives: The aim of this study was to determine whether retinoblastoma-like 2 (RBL2/p130), an emerging CDK2 inhibitor, regulates anthracycline sensitivity in the heart.

Methods: Rbl2^-/- mice and Rbl2^+/+ littermates received DOX (5 mg/kg/wk for 4 weeks intraperitoneally, 20 mg/kg cumulative). Heart function was monitored with echocardiography. The association of RBL2 genetic variants with anthracycline cardiomyopathy was evaluated in the SJLIFE (St. Jude Lifetime Cohort Study) and CPNDS (Canadian Pharmacogenomics Network for Drug Safety) studies.

Results: The loss of endogenous Rbl2 increased basal CDK2 activity in the mouse heart. Mice lacking Rbl2 were more sensitive to DOX-induced cardiotoxicity, as evidenced by rapid deterioration of heart function and loss of heart mass. The disruption of Rbl2 exacerbated DOX-induced mitochondrial damage and cardiomyocyte apoptosis. Mechanistically, Rbl2 deficiency enhanced CDK2-dependent activation of forkhead box O1 (FOXO1), leading to up-regulation of the proapoptotic protein Bim. The inhibition of CDK2 desensitized Rbl2-depleted cardiomyocytes to DOX. In wild-type cardiomyocytes, DOX exposure induced Rbl2 expression in a FOXO1-dependent manner. Importantly, the rs17800727 G allele of the human RBL2 gene was associated with reduced anthracycline cardiotoxicity in childhood cancer survivors.

Conclusions: Rbl2 is an endogenous CDK2 inhibitor in the heart and represses FOXO1-mediated proapoptotic gene expression. The loss of Rbl2 increases sensitivity to DOX-induced cardiotoxicity. Our findings suggest that RBL2 could be used as a biomarker to predict the risk of cardiotoxicity before the initiation of anthracycline-based chemotherapy.

Keywords: cancer therapy; cardiomyopathy; cardiotoxicity; cell cycle; cell death; doxorubicin; genetics; heart failure; mechanisms; tumor.

Abstract

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