PRKDC: New biomarker and drug target for checkpoint blockade immunotherapy

Kien Thiam Tan, Chun Nan Yeh, Yu Chan Chang, Jen Hao Cheng, Wen Liang Fang, Yi Chen Yeh, Yu Chao Wang, Dennis Shin Shian Hsu, Chiao En Wu, Jiun I. Lai, Peter Mu Hsin Chang, Ming Han Chen, Meng Lun Lu, Shu Jen Chen, Yee Chao, Michael Hsiao, Ming Huang Chen*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

32 Scopus citations

Abstract

Background Immunological checkpoint blockade is effective in treating various malignancies. Identifying predictive biomarkers to assist patient selection for immunotherapy has become a priority in both clinical and research settings. Methods Mutations in patients who responded to immunotherapy were identified through next-generation sequencing. Relationships among protein kinase, DNA-activated, catalytic polypeptide (PRKDC) mutations, mutation load and microsatellite instability (MSI) were analyzed using datasets from The Cancer Genome Atlas. These relationships were validated by conducting an in vitro study and by using tissue samples from 34 patients with gastric cancer. The CT26 animal model was used to evaluate the role of PRKDC as a predictive biomarker and the efficacy of the DNA-PK inhibitor. Results From the published literature, we found that among patients whose tumors harbored PRKDC mutations, 75%, 53.8%, and 50% of those with lung cancer, melanoma, and renal cell carcinoma, respectively, responded to immunotherapy. Most of these mutations were truncating and located in functional domains or in a destabilizing PRKDC protein structure. Additional analysis showed that a PRKDC mutation was significantly associated with a high mutation load in cervical cancer, colon adenocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, gastric adenocarcinoma and endometrial cancer. Patients with gastric cancer or colon cancer harboring PRKDC mutations were also highly associated with MSI-high status. Finally, we found that knockout PRKDC or DNA-PK inhibitor (PRKDC encodes the catalytic subunit of DNA-dependent protein kinase) enhanced the efficacy of the anti-programmed cell death protein one pathway monoclonal antibody in the CT26 animal model. Conclusions PRKDC is not only a predictive biomarker but also a drug target for immune checkpoint inhibitors.

Original languageEnglish
Article numbere000485
JournalJournal for ImmunoTherapy of Cancer
Volume8
Issue number1
DOIs
StatePublished - 01 04 2020

Bibliographical note

Publisher Copyright:
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Keywords

  • biomarkers, tumor
  • gastrointestinal neoplasms
  • genome instability
  • immunotherapy

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