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The effect was very similar to that of an equivalent concentration of UCN.Agents that can abrogate the G checkpoint, such as methylxanthines, phosphatase inhibitors, or UCN, previously have been identified, but the mechanism by which they affect checkpoint regulation is poorly understood.Indeed, we also observed that higher concentrations of SB, above mM, did begin to inhibit cell proliferation in these longerterm assays.Nevertheless, we specifically chose subcytotoxic concentrations of SB and topotecan in these assays to maximally demonstrate their combined effects.These data suggest that it may not be necessary to completely abrogate G arrest to have a significant impact on the ability of cells to handle DNA damage and survive over several days.In the clonogenic assay, we sought to compare SB and UCN directly, using conditions reported previously for UCN. Both SB and UCN, at nM, enhanced the cytotoxicity of camptothecin, and the maximal enhancement was apparent at the lowest doses of camptothecin.A second checkpoint kinase has been identified very recently.Cells were then harvested, reseeded, and incubated for days.Colony formation was measured by staining with methylene blue and counting.Survival was calculated based on the colony number for cells treated with vehicle only.Nevertheless, it is unlikely that these two kinases are completely redundant.Moreover, these kinases may have different additional substrates other than cdcC.Data were generated in triplicate and are shown as the average value; bars, SE.Click on Request Permissions which will take you to the Copyright Clearance Centers Downloaded from cancerres.aacrjournals.org on September. American Association for Cancer Research. We further demonstrate that DDR inhibition activated the STINGTBKIRF innate immune pathway, leading to increased levels of chemokines such as CXCL and CCL that induced activation and function of cytotoxic T lymphocytes.Knockdown of cGAS and STING successfully reversed the antitumor effect of combined inhibition of DDR and PDL.Our results defi ne previously unrecognized innate immune pathwaymediated immunomodulatory functions of DDR proteins and provide a rationale for combining PARPCHK inhibitors and immunotherapies in SCLC.The most commonly used therapeutic approaches use antibodies against inhibitory signaling molecules expressed on tumor and immune cells.Common targets include the immune checkpoints PD, PDL, and CTLA for melanoma, several such immune checkpoint blockade agents have been approved for patients with advanced cancers, including nonsmall cell lung cancer. Thus, efforts are under way to develop new therapeutic strategies with novel drug combinations to enhance the antitumor effi cacy of ICB.Consistent with this, clinical trials investigating PD or PDL blockade in patients with SCLC have shown low overall response rates. Recent studies have demonstrated the potential of targeting the DNA damage response, including drugs targeting PARP and checkpoint kinase. Several DDR inhibitors have been developed and are now either approved for the treatment of other cancers. Although best known for its functions in repairing DNA damage and controlling the cell cycle, the DDR pathway has also been shown to be involved in the antitumor immune response. For example, the PARP inhibitor olaparib was recently reported to show a synergistic effect with PDL blockade in triplenegative breast cancer in preclinical models. However, little is currently known regarding the mechanistic interactions between DDR targeting and response to ICB, as well as the immuneactivating properties of DDR targeting.

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