Researchers at UHN’s Princess Margaret Cancer Centre (PM) have identified a new target that could enhance the effectiveness of radiation therapy for small cell lung cancer (SCLC).
SCLC is an aggressive form of lung cancer, and most patients are diagnosed when the disease is already at an advanced stage, when treatment options are limited. The current standard of care includes chemotherapy and immunotherapy. While initial response rates are often high, many patients relapse due to acquired treatment resistance.
Radiation therapy, when used in combination with chemotherapy (and sometimes immunotherapy), can improve survival for some patients. This benefit might be further enhanced by combining radiation therapy with drugs called radiosensitizers, which increases cancer cells' vulnerablity to radiation.
To identify potential radiosensitizers for SCLC, researchers led by Dr. Benjamin Lok, Clinician Scientist at PM, performed a genetic screen using a gene-editing tool called CRISPR to create mutations in genes of known cancer drug targets.
From this screen, the gene HDAC3 (histone deacetylase 3) emerged as a promising candidate. HDAC3 encodes a protein involved in modifying DNA and regulating gene expression, DNA replication, and repair. It is also known to be implicated in various cancers, including gastric and ovarian cancers.
When researchers removed HDAC3 function, either by silencing the gene or using a drug called RGFP96, SCLC cells became more sensitive to radiation. This radiosensitizing effect was also observed in cancer models, where tumour growth was inhibited.
The team also explored the mechanism underlying HDAC3’s role in radiation sensitivity. They found that loss of HDAC3 resulted in DNA that was more accessible, or open, to radiation, leading to increases in DNA damage. These cells also had more DNA breaks and a reduced ability to repair them, resulting in persistent damage.
Together, these findings suggest that targeting HDAC3 could improve the effectiveness of existing cancer treatments for SCLC, potentially serving as a radiosensitization strategy.
Ujas A. Patel, is a former Master’s student at the University of Toronto and co-first author of the study.
Mary Y. Shi, is a former Master’s student at the University of Toronto and co-first author of the study.
Dr. Benjamin Lok, Clinician Scientist at UHN's Princess Margaret Cancer Centre and Associate Professor in the Department of Medical Biophysics, Radiation Oncology, and Institute of Medical Science at the University of Toronto, is the corresponding author of the study.
This work was supported by the Terry Fox Research Institute, Canada Foundation for Innovation, Cancer Research Society, Canadian Institutes of Health Research, National Cancer Institute, Clinical and Translational Science Center at Weill Cornell Medical Center/Memorial Sloan Kettering Cancer Center, Government of Ontario, and The Princess Margaret Cancer Foundation.
Dr. Benjamin Lok reports institutional grants from Pfizer and institutional grants, personal fees, and nonfinancial support from AstraZeneca, and personal fees from Daiichi-Sankyo outside the submitted work. For a complete list of competing interests, see the manuscript.
Patel UA, Shi MY, Kazan JM, Nixon KCJ, Ran X, Nair SN, Huang O, Song L, Aparnathi MK, He MY, Bakhtiari M, Krishnan R, Hessenow RK, Philip V, Ketela T, Jendrossek V, Hakem R, He HH, Kridel R, Lok BH. CRISPR Screen Identifies HDAC3 as a Novel Radiosensitizing Target in Small Cell Lung Cancer. Mol Cancer Ther. 2025 Sep 25:OF1-OF13. doi: 10.1158/1535-7163.MCT-24-0861. Epub ahead of print.