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ResearchIn-Press PreviewOncologyTherapeutics Open Access | 10.1172/JCI172716
1Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, United States of America
2Department of Pathology, The Second Xiangya Hospital, South Central University, Changsha, China
3Department of Internal Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
Find articles by Chen, Z. in: JCI | PubMed | Google Scholar
1Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, United States of America
2Department of Pathology, The Second Xiangya Hospital, South Central University, Changsha, China
3Department of Internal Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
Find articles by Vallega, K. in: JCI | PubMed | Google Scholar
1Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, United States of America
2Department of Pathology, The Second Xiangya Hospital, South Central University, Changsha, China
3Department of Internal Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
Find articles by Wang, D. in: JCI | PubMed | Google Scholar
1Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, United States of America
2Department of Pathology, The Second Xiangya Hospital, South Central University, Changsha, China
3Department of Internal Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
Find articles by Quan, Z. in: JCI | PubMed | Google Scholar
1Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, United States of America
2Department of Pathology, The Second Xiangya Hospital, South Central University, Changsha, China
3Department of Internal Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
Find articles by Fan, S. in: JCI | PubMed | Google Scholar
1Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, United States of America
2Department of Pathology, The Second Xiangya Hospital, South Central University, Changsha, China
3Department of Internal Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
Find articles by Wang, Q. in: JCI | PubMed | Google Scholar
1Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, United States of America
2Department of Pathology, The Second Xiangya Hospital, South Central University, Changsha, China
3Department of Internal Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
Find articles by Leal, T. in: JCI | PubMed | Google Scholar
1Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, United States of America
2Department of Pathology, The Second Xiangya Hospital, South Central University, Changsha, China
3Department of Internal Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
Find articles by Ramalingam, S. in: JCI | PubMed | Google Scholar |
1Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, United States of America
2Department of Pathology, The Second Xiangya Hospital, South Central University, Changsha, China
3Department of Internal Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
Find articles by Sun, S. in: JCI | PubMed | Google Scholar
Published March 7, 2024 - More info
Development of effective strategies to manage the inevitable acquired resistance to osimertinib, an approved 3rd generation EGFR inhibitor for the treatment of EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC), is urgently needed. This study reported that the DNA topoisomerase II (Topo II) inhibitors, doxorubicin and etoposide (VP-16) synergistically decreased cell survival with enhanced induction of DNA damage and apoptosis in osimertinib-resistant cells, suppressed the growth of osimertinib-resistant tumors, and delayed the emergence of osimertinib acquired resistance. Mechanistically, osimertinib decreased Topo IIα levels in EGFRm NSCLC cells by facilitating FBXW7-mediated proteasomal degradation, resulting in induction of DNA damage; these effects were lost in osimertinib-resistant cell lines possessing elevated levels of Topo IIα. Topo IIα elevation was also detected in the majority of EGFRm NSCLC tissues relapsed from EGFR-TKI treatment. Enforced expression of an ectopic TOP2A gene in sensitive EGFRm NSCLC cells conferred resistance to osimertinib, whereas knockdown of TOP2A in osimertinib-resistant cell lines restored their response to undergo osimertinib-induced DNA damage and apoptosis. Together, these results reveal an essential role of Topo IIα inhibition in mediating the therapeutic efficacy of osimertinib against EGFRm NSCLC, providing scientific rationale for targeting Topo II to manage acquired resistance to osimertinib.