1. Academic Validation
  2. BRD4 Levels Determine the Response of Human Lung Cancer Cells to BET Degraders That Potently Induce Apoptosis through Suppression of Mcl-1

BRD4 Levels Determine the Response of Human Lung Cancer Cells to BET Degraders That Potently Induce Apoptosis through Suppression of Mcl-1

  • Cancer Res. 2020 Jun 1;80(11):2380-2393. doi: 10.1158/0008-5472.CAN-19-3674.
Dan Zong 1 2 Jiajia Gu 1 2 Giovanna C Cavalcante 2 3 Weilong Yao 2 4 Guojing Zhang 2 Shaomeng Wang 5 Taofeek K Owonikoko 2 Xia He 6 Shi-Yong Sun 7
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, P. R. China.
  • 2 Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia.
  • 3 Laboratory of Human and Medical Genetics, Federal University of Pará, Belém, Pará, Brazil.
  • 4 Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China.
  • 5 Departments of Medicinal Chemistry, Pharmacology and Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • 6 Department of Radiation Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, P. R. China. ssun@emory.edu hexiabm@163.com.
  • 7 Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia. ssun@emory.edu hexiabm@163.com.
Abstract

Lung Cancer consists of approximately 80% non-small cell lung Cancer (NSCLC) and 20% small cell lung Cancer (SCLC) and remains the leading cause of cancer-related deaths worldwide despite advances in early diagnosis, targeted therapy, and immunotherapy. Thus, novel therapies are still urgently needed. Bromodomain and extraterminal (BET) proteins, primarily comprised of BRD2, BRD3, and BRD4 proteins, function as epigenetic readers and master transcription coactivators and are now recognized Cancer therapeutic targets. BET degraders such as ZBC260 and dBET represent a novel class of BET inhibitors that act by inducing BET degradation. The current study demonstrates the therapeutic efficacies of BET degraders, particularly ZBC260, against lung Cancer, as well as understanding the underlying mechanisms and identifying molecular markers that determine cell sensitivity to BET degraders. A panel of NSCLC cell lines possessed similar response patterns to ZBC260 and dBET but different responses to BET inhibitor JQ-1. BRD levels, particularly BRD4, correlated positively with high sensitivity to BET degraders but not to JQ-1. BET degraders potently induced Apoptosis in sensitive NSCLC cells and were accompanied by reduction of Mcl-1 and c-FLIP levels, which are critical for mediating induction of Apoptosis and enhancement of TRAIL-induced Apoptosis. Accordingly, ZBC260 exerted more potent activity than JQ-1 in vivo against the growth of NSCLC xenografts and patient-derived xenografts. These findings warrant future clinical validation of the efficacy of BET degraders in NSCLC, particularly those with high levels of BRD proteins, especially BRD4. SIGNIFICANCE: The current study demonstrates the potential of novel BET degraders in the treatment of lung Cancer and warrants clinical validation of BET degraders in lung Cancer with high levels of BRD4.

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