DNA topoisomerases and their poisoning by anticancer and antibacterial drugs.

Recent molecular studies have expanded the biological contexts in which topoisomerase II (TOP2) has crucial functions, including DNA replication, transcription and chromosome segregation. Although the biological functions of TOP2 are important for ensuring genomic integrity, the ability to interfere with TOP2 and generate enzyme-mediated DNA damage is an effective strategy for cancer chemotherapy. The molecular tools that have allowed an understanding of the biological functions of TOP2 are also being applied to understanding the details of drug action. These studies promise refined targeting of TOP2 as an effective anticancer strategy.

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Targeting DNA topoisomerase II in cancer chemotherapy

Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.

Identification of the molecular basis of doxorubicin-induced cardiotoxicity

The goal of this study is to give a brief background on the literature supporting the PharmGKB pathway about doxorubicin action, and provides a summary of this active area of research. The reader is referred to recent in-depth reviews [1–4] for more detailed discussion of this important and complex pathway. Doxorubicin is an anthracyline drug first extracted from Streptomyces peucetius var. caesius in the 1970’s and routinely used in the treatment of several cancers including breast, lung, gastric, ovarian, thyroid, non-Hodgkin’s and Hodgkin’s lymphoma, multiple myeloma, sarcoma, and pediatric cancers [5–7]. A major limitation for the use of doxorubicin is cardiotoxicity, with the total cumulative dose being the only criteria currently used to predict the toxicity [4,8]. As there is evidence that the mechanisms of anticancer action and of cardiotoxicity occur through different pathways there is hope for the development of anthracycline drugs with equal efficacy but reduced toxicity [4]. Knowledge of the pharmacogenomics of these pathways may eventually allow for future selection of patients more likely to achieve efficacy at lower doses or able to withstand higher doses with lesser toxicity. We present here graphical representations of the candidate genes for the pharmacogenomics of doxorubicin action in a stylized cancer cell (Fig. 1) and toxicity in cardiomyocytes (Fig. 2), and a table describing the key variants examined so far.






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Fig. 1


Graphical representation of the candidate genes involved in the pharmacodynamics of doxorubicin in a stylized cancer cell. A fully interactive version of this pathway is available online at PharmGKB at http://www.pharmgkb.org/do/serve?objId=PA165292163o ROS, reactive oxygen species.

Doxorubicin pathways: pharmacodynamics and adverse effects

Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management.


 Epithelial to mesenchymal transition (EMT) plays an important role in metastasis and chemoresistance. However, targeting EMT has been challenging due to the complex and redundant EMT signaling pathways. Moreover, EMT inhibition would unequivocally promote its reversed process, mesenchymal to epithelial transition (MET), which also favors malignancy progression. To solve this EMT targeting paradox, we proposed to target the ability of tumor cells to oscillate between epithelial and mesenchymal states, the epithelial to mesenchymal plasticity (EMP), which encompasses both EMT and MET. Using a SnailCre-ERT2 mediated EMT lineage-tracing model, we confirmed the involvement of EMP in chemoresistant metastasis of breast cancer. Single-cell transcriptome analyses of tumor cells in the transitioning phases of EMT or MET consistently revealed that ribosome biogenesis (RiBi) was specifically elevated regardless of their destined phenotypical fates. Further analyses delineated that the upregulation of RiBi and the subsequent nascent protein synthesis via the intensified ERK and mTOR signalings were vital for cancer cells to transit between epithelial and mesenchymal states. Importantly, inhibiting the excessive RiBi by either genetic or pharmacological means impaired EMP, as both EMT and MET processes were impeded, leading to significantly reduced metastatic outgrowth of chemoresistant tumor cells. Our studies revealed that elevated RiBi is required for tumor cells to “Ping Pong” between epithelial and mesenchymal states. Targeting the EMP via RiBi inhibition provides a feasible strategy to improve therapies for advanced breast cancers.
 Citation Format: Yi Ban, Wenjuan Dong, Yue Zou, Sharrell B. Lee, Jianting Sheng, Yuliang Cao, Stephen T.C. Wong, Dingcheng Gao. Targeting epithelial-mesenchymal plasticity via ribosome biogenesis inhibition reduces chemoresistant metastasis of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 963.

Abstract 963: Targeting epithelial-mesenchymal plasticity via ribosome biogenesis inhibition reduces chemoresistant metastasis of breast cancer

Epithelial-to-mesenchymal transition (EMT) contributes significantly to chemotherapy resistance and remains a critical challenge in treating advanced breast cancer. The complexity of EMT, involving redundant pro-EMT signaling pathways and its paradox reversal process, mesenchymal-to-epithelial transition (MET), has hindered the development of effective treatments. In this study, we utilized a Tri-PyMT EMT lineage-tracing model and single-cell RNA sequencing (scRNA-seq) to comprehensively analyze the EMT status of tumor cells. Our findings revealed elevated ribosome biogenesis (RiBi) during the transitioning phases of both EMT and MET processes. RiBi and its subsequent nascent protein synthesis mediated by ERK and mTOR signalings are essential for EMT/MET completion. Importantly, inhibiting excessive RiBi genetically or pharmacologically impaired the EMT/MET capability of tumor cells. Combining RiBi inhibition with chemotherapy drugs synergistically reduced metastatic outgrowth of epithelial and mesenchymal tumor cells under chemotherapies. Our study suggests that targeting the RiBi pathway presents a promising strategy for treating patients with advanced breast cancer. Significance This study uncovers the crucial involvement of ribosome biogenesis (RiBi) in the regulation of epithelial and mesenchymal state oscillations in breast cancer cells, which plays a major role in the development of chemoresistant metastasis. By proposing a novel therapeutic strategy targeting the RiBi pathway, the study offers significant potential to enhance treatment efficacy and outcomes for patients with advanced breast cancer. This approach could help overcome the limitations of current chemotherapy options and address the complex challenges posed by EMT-mediated chemoresistance.

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Targeting Ribosome Biogenesis as a Novel Therapeutic Approach to Overcome EMT-related Chemoresistance in Breast Cancer

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Yi Ban

Papers

Abstract 963: Targeting epithelial-mesenchymal plasticity via ribosome biogenesis inhibition reduces chemoresistant metastasis of breast cancer

Targeting Ribosome Biogenesis as a Novel Therapeutic Approach to Overcome EMT-related Chemoresistance in Breast Cancer

Author Correction: Radiation-activated secretory proteins of Scgb1a1+ club cells increase the efficacy of immune checkpoint blockade in lung cancer