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Targeting NHEJ activates STING signaling through MYC degradation to boost antitumor immunity in SCLC
Subhamoy Chakraborty1, Andrew Elliott2, Utsav Sen3
1Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
Abstract:
Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Paradoxically, this tumor displays a high mutation burden; however, a modest response to immunotherapy. Improving Immunotherapy response in SCLC patients remains an unmet need. Here, we report that across 24 tumor types, including over 179,000 real-world patient tumors, SCLC has the highest expression of nonhomologous end joining (NHEJ) DNA repair regulator PRKDC (DNAPKcs). High PRKDC expression predicts poor response to immunotherapy in SCLC. DNAPKcs depletion causes activation of cGAS/STING pathway due to cytoplasmic accumulation of double-stranded DNA, inducing immunogenicity and enhancing sensitivity of SCLC models to immunotherapy. Analyses in SCLC cell lines and mouse models shows that depletion of DNAPKcs leads to proteasomal degradation of MYC via GSK3β pathway. We show that DNAPKcs upregulation contributes to immunotherapy resistance and DNAPKcs inhibition represents a promising therapeutic strategy to induce antitumor immunity and potentiate immunotherapy efficacy in immunologically suppressed SCLC.
Insights
Small-cell lung cancer (SCLC) shows high PRKDC (DNAPKcs) expression, hindering immunotherapy. Inhibiting DNAPKcs activates immune responses, improving SCLC immunotherapy efficacy.
Area of Science:
- Oncology
- Cancer Immunology
- DNA Repair
Background:
- Small-cell lung cancer (SCLC) is highly lethal despite a high mutation burden.
- Current immunotherapies offer modest benefits for SCLC patients, highlighting an unmet clinical need.
- SCLC exhibits the highest expression of the DNA repair protein PRKDC (DNAPKcs) among 24 tumor types.
Purpose of the Study:
- To investigate the role of PRKDC (DNAPKcs) in SCLC immunotherapy resistance.
- To explore the potential of DNAPKcs inhibition as a therapeutic strategy for SCLC.
Main Methods:
- Analysis of PRKDC expression in over 179,000 real-world patient tumors.
- Depletion of DNAPKcs in SCLC cell lines and mouse models.
- Investigation of downstream signaling pathways, including cGAS/STING and MYC degradation.
Main Results:
- High PRKDC expression correlates with poor immunotherapy response in SCLC.
- DNAPKcs depletion activates the cGAS/STING pathway by increasing cytoplasmic double-stranded DNA.
- DNAPKcs inhibition leads to MYC proteasomal degradation via the GSK3β pathway, enhancing immunogenicity.
- Depletion of DNAPKcs sensitizes SCLC models to immunotherapy.
Conclusions:
- PRKDC (DNAPKcs) upregulation contributes to immunotherapy resistance in SCLC.
- Inhibition of DNAPKcs is a promising strategy to enhance antitumor immunity.
- Targeting DNAPKcs can potentiate immunotherapy efficacy in SCLC.
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