2. Academic Validation
  3. The novel BET degrader, QCA570, is highly active against the growth of human NSCLC cells and synergizes with osimertinib in suppressing osimertinib-resistant EGFR-mutant NSCLC cells

The novel BET degrader, QCA570, is highly active against the growth of human NSCLC cells and synergizes with osimertinib in suppressing osimertinib-resistant EGFR-mutant NSCLC cells

  • Am J Cancer Res. 2022 Feb 15;12(2):779-792.
Chaoyuan Liu 1 2,  Luxi Qian 2 3,  Karin A Vallega 2,  Guangzhi Ma 2 4,  Dan Zong 2 3,  Luxiao Chen 5,  Shaomeng Wang 6,  Suresh R Ramalingam 2,  Zhaohui Qin 5,  Shi-Yong Sun 2
Affiliations

Affiliations

  • 1 Department of Oncology, The Second Xiangya Hospital, Central South University Changsha 410011, Hunan, China.
  • 2 Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute Atlanta, GA 30322, USA.
  • 3 Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University Nanjing 210009, Jiangsu, China.
  • 4 Department of Thoracic Surgery, West China Hospital, Sichuan University Chengdu 610041, Sichuan, China.
  • 5 Department of Biostatistics and Bioinformatics, Rollins School of Public Health of Emory University Atlanta, GA 30322, USA.
  • 6 Department of Medicinal Chemistry, University of Michigan Ann Arbor, MI 48109, USA.
PMID: 35261801
Abstract

Lung Cancer remains the leading cause of Cancer deaths worldwide despite advances in knowledge in Cancer biology and options of various targeted therapies. Efforts in identifying innovative and effective therapies are still highly appreciated. Targeting bromodomain and extra terminal (BET) proteins that function as epigenetic readers and master transcription coactivators is now a potential Cancer therapeutic strategy. The current study evaluates the therapeutic efficacies of the novel BET degrader, QCA570, in lung Cancer and explores its underlying mechanisms. QCA570 at low nanomolar ranges effectively decreased the survival of a panel of human lung Cancer cell lines with induction of Apoptosis in vitro. As expected, it potently induced degradation of BET proteins including BRD4, BRD3 and BRD2. Moreover, it potently decreased Mcl-1 levels due to transcriptional suppression and protein degradation; this event is critical for mediating Apoptosis induced by QCA570. Moreover, QCA570 synergized with osimertinib in suppressing the growth of osimertinib-resistant cells in vitro and in vivo, suggesting potential in overcoming acquired resistance to osimertinib. These preclinical findings support the potential of QCA570 in treatment of lung Cancer either as a single agent or in combination with Others.

Keywords

BET; QCA570; apoptosis; degradation; lung cancer; osimertinib.

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