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Identification of pharmacodynamic biomarkers and common molecular mechanisms of response to genotoxic agents in cancer cell lines

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Abstract

Purpose

Genotoxic agents (GAs) including cisplatin, doxorubicin, gemcitabine, and topotecan are often used in cancer treatment. However, the response to GAs is variable among patients and predictive biomarkers are inadequate to select patients for treatment. Accurate and rapid pharmacodynamics measures of response can, thus, be useful for monitoring therapy and improve clinical outcomes.

Methods

This study focuses on integrating a database of genome-wide response to treatment (The NCI Transcriptional Pharmacodynamics Workbench) with a database of baseline gene expression (GSE32474) for the NCI-60 cell lines to identify mechanisms of response and pharmacodynamic (PD) biomarkers.

Results and conclusions

Our analysis suggests that GA-induced endoplasmic reticulum (ER) stress may signal for GA-induced cell death. Reducing the uptake of GA, activating DNA repair, and blocking ER-stress induction cooperate to prevent GA-induced cell death in the GA-resistant cells. ATF3, DDIT3, CARS, and PPP1R15A appear as possible candidate PD biomarkers for monitoring the progress of GA treatment. Further validation studies on the proposed intrinsic drug-resistant mechanism and candidate genes are needed using in vivo data from either patient-derived xenograft models or clinical chemotherapy trials.

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Acknowledgements

The authors would like to thank Dr. Julia Krushkal for reading the manuscript and for providing helpful feedback.

Funding

This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

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Authors and Affiliations

  1. Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD, 20850, USA

    Dong-Joon Min, Yingdong Zhao, Alida Palmisano & Richard M. Simon

  2. Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA

    Anne Monks & Curtis Hose

  3. Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, 20892, USA

    Beverly A. Teicher

  4. Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, 20892, USA

    James H. Doroshow

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  1. Dong-Joon Min
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Min, DJ., Zhao, Y., Monks, A. et al. Identification of pharmacodynamic biomarkers and common molecular mechanisms of response to genotoxic agents in cancer cell lines. Cancer Chemother Pharmacol 84, 771–780 (2019). https://doi.org/10.1007/s00280-019-03898-z

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