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Ref Type Journal Article
PMID (32238472)
Authors Tan KT, Yeh CN, Chang YC, Cheng JH, Fang WL, Yeh YC, Wang YC, Hsu DS, Wu CE, Lai JI, Chang PM, Chen MH, Lu ML, Chen SJ, Chao Y, Hsiao M, Chen MH
Title PRKDC: new biomarker and drug target for checkpoint blockade immunotherapy.
Journal Journal for immunotherapy of cancer
Vol 8
Issue 1
Date 2020 Mar
URL
Abstract Text 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.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.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.PRKDC is not only a predictive biomarker but also a drug target for immune checkpoint inhibitors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown colorectal cancer not applicable MSC2490484A + unspecified PD-L1 antibody Preclinical Actionable In a preclinical study, the combination of MSC2490484A and an unspecified PD-L1 antibody resulted in greater inhibition of tumor growth compared to the unspecified PD-L1 antibody alone in a colorectal cancer cell line mouse model (PMID: 32238472). 32238472