Because prexasertib, olaparib, and other PARP inhibitors are already in clinical trials for SCLC, we expect that these findings have the potential for rapid translation into the clinic.All compounds were dissolved in dimethyl sulfoxide for in vitro treatments.For the PARP inhibitor experiments, mice received one of the buy Tiopronin following treatments: once per week; or combination of olaparib and antiPDL.Tumors were collected for singlecell preparation for flow cytometry, snapfrozen in liquid nitrogen for protein isolation, or fixed in paraformaldehyde in PBS at C and processed for paraffin histologic analysis.Sections of paraffinembedded tissues were stained with HE and collected for IHC.The RPP tripleknockout mouse model for SCLC has been previously described.The mice were imaged for luciferase luminescence using an IVIS CCD camera.The mice were separated into treatment groups to ensure all cohorts had comparable levels of luminescence, which is proportional to the amount of tumors in the mouse.The CHK inhibitor prexasertib was injected subcutaneously at the nape of the neck every hours for days in a row, for week. Triplicate PCR reactions were run on ABI according to the manufacturers instructions.Negative controls were included for every primer set, and GAPDH was used as the positive control.The costs of publication of this article were defrayed in part by the payment of page charges.Primary, adaptive, and acquired resistance to cancer immunotherapy.Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in smallcell lung cancer.Supplementary Material Access the most recent version of this article at: doi. Click on Request Permissions which will take you to the Copyright Clearance Centers Downloaded from cancerdiscovery.aacrjournals.org on September. American Association for Cancer Research. One of the several cellular processes that could explain this interindividual variation in risk is DRC, the focus of this paper.Genetic instability, which drives tumorigenesis, is itself fuelled by DNA damage and by errors made by the DNA repair machinery.DNA repair is a ubiquitous defense mechanism that is critical to maintaining the integrity of the genome and repairing the damage from exposure to exogenous environmental xenobiotics, as well as to endogenous damage or spontaneous disintegration of chemical bonds in DNA.There is quite substantial interindividual variation in DRC within a population.At the extreme end of this spectrum are patients with XP, who have a defect in NER, and who exhibit thousandfold increased risks of skin cancer.There is a larger subgroup with reduced DRC who are likely to be at increased cancer risk, but are phenotypically normal.The challenge for molecular epidemiological research is to be able to identify this atrisk subgroup, who could be targeted for the most intensive behavior modification changes and screening interventions.The costs of publication of this article were defrayed in part by the payment of page charges.Our approach to risk assessment is multitiered, beginning with a detailed epidemiological assessment in casecontrol studies, followed by the application of an array of phenotypic and genotypic markers of genetic susceptibility.Therefore, measuring the expression level of damaged reporter genes using hostcell reactivation is the assay of choice.This assay uses undamaged cells, is relatively fast, and is an objective way of measuring intrinsic cellular repair.