Researchers from the University of Texas MD Anderson Cancer Center have discovered that an immune checkpoint inhibitor and targeted therapy that inhibits normal DNA damage repair (DDR) can significantly inhibit small cell lung cancer in mice. This means a potential new method for treating patients with such malignant cancers. The study, recently published in Cancer Discovery, showed that the PARP inhibitor olaparib and other DDR inhibitors can rapidly induce an immune response among SCLC cells that were previously insensitive to immunotherapy.

As viewed by Dr. Lauren Averett Byers, associate professor of internal medicine for chest and head and neck cancer, SCLC is one of the most malignant cancers, accounting for about 15% of all lung cancer patients, and there are 30,000 new cases every year in the United States. The standard treatment for advanced SCLC is chemotherapy, but recurrence is common, and the average survival of patients is only 12 months. Recently the combination of immunotherapy and chemotherapy has become a new standard, but only a small number of patients can benefit from new combination therapies.

Although immunotherapy has subverted the traditional approach to lung cancer, it is found that small cell lung cancer cells can quickly avoid the immune system, so the response rates among patient are low. In this sense, there is still much room for improvement.

Previously, researchers found that DDR pathways were activated in SCLC, and inhibition of these pathways (such as PARP and CHK1 inhibitors) can effectively treat animal SCLC models. In addition, the higher the degree of DNA damage, the higher the response of the tumor to immunotherapy.

As predicted, if PARP inhibitors or other drugs that cause DNA damage are combined with immunotherapy, cells are more likely to respond more to immunotherapy. It is observed that after using PARP or CHK1 inhibitors in combination with immunotherapy, the tumors became significantly smaller, and the tumors of some mice even disappeared completely. The combination of PARP inhibitor and immunotherapy completely abolished the tumor in mice in a week or so, so no further analysis was possible, and the combination of CHK1 inhibitors was used. This resulted in the complete disappearance of tumors in 60% of mice.

The researchers found that DDR inhibitors can activate the immune response in mice, thereby increasing the number of immune cells that kill tumor cells. This process is controlled by a pathway called STING, which is usually responsible for detecting viral or bacterial infection signals. In this study, the STING pathway responds to DNA damage by activating the immune system, ultimately making SCLC cells more sensitive to immunotherapy.

The results of this study are really amazing, because the combination therapy has significantly enhanced the anti-cancer effect. Such a finding will surely bring about great benefit to patients.

Clinical trials to test PARP inhibitors or immunotherapy for SCLC are ongoing. Researchers of this study hope to start clinical trials at the end of this year to learn more about the efficacy of this combination therapy in humans. They also hope that this therapy can be produced in other cancer patients with increased DNA damage (such as BRCA-mutant breast cancer and ovarian cancer patients).

Lauren Averett Byers et al. Evading the STING: LKB1 Loss Leads to STING Silencing and Immune Escape in KRAS-Mutant Lung Cancers. Cancer Discovery.DOI: 10.1158/2159-8290

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