DNA topoisomerase II inhibition potentiates osimertinib’s therapeutic efficacy in EGFR-mutant non–small cell lung cancer models
Zhen Chen, … , Suresh S. Ramalingam, Shi-Yong Sun
Zhen Chen, … , Suresh S. Ramalingam, Shi-Yong Sun
Published March 7, 2024
Citation Information: J Clin Invest. 2024;134(10):e172716. https://doi.org/10.1172/JCI172716.
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Research Article Oncology

DNA topoisomerase II inhibition potentiates osimertinib’s therapeutic efficacy in EGFR-mutant non–small cell lung cancer models

Abstract

Development of effective strategies to manage the inevitable acquired resistance to osimertinib, a third-generation EGFR inhibitor for the treatment of EGFR-mutant (EGFRm) non–small cell lung cancer (NSCLC), is urgently needed. This study reports that DNA topoisomerase II (Topo II) inhibitors, doxorubicin and etoposide, 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 that possess elevated levels of Topo IIα. Increased Topo IIα levels were also detected in the majority of tissue samples from patients with NSCLC after relapse from EGFR tyrosine kinase inhibitor 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 susceptibility to 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.

Authors

Zhen Chen, Karin A. Vallega, Dongsheng Wang, Zihan Quan, Songqing Fan, Qiming Wang, Ticiana Leal, Suresh S. Ramalingam, Shi-Yong Sun

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Figure 7

Osimertinib combined with a Topo II inhibitor synergistically decreases the survival of EGFRm NSCLC cell lines with primary resistance to osimertinib expressing elevated levels of Topo IIα, eliminates DTCs, and regresses different EGFRm PDX tumors in vivo with long-term remissions.

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Osimertinib combined with a Topo II inhibitor synergistically decreases ...
(A) Detection of basal levels of Topo IIα in the indicated cell lines with Western blotting. (B and C) The given cell lines were exposed to varied concentrations of osimertinib (Osim), DXR, or VP-16 alone as indicated and the combination of osimertinib with DXR or VP-16. After 3 days, cell numbers were determined with the SRB assay. The data represent mean ± SD of 4 replicate determinations. (D) The indicated cell lines seeded in 12-well plates were treated with 50 nM osimertinib, 150 nM VP-16, or a combination; these treatments were repeated with fresh medium every 2 days. After 5 or 10 days, the cells were fixed, stained with crystal violet dye, and images were taken. (E–G) The indicated PDXs in nude mice (6 tumors/group) were treated with vehicle, 5 mg/kg osimertinib (daily, oral gavage), 1 mg/kg VP-16 (daily, i.p.), or the combination of osimertinib and VP-16. The data represent mean ± SEM of 6 tumors.