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- W2891208504 abstract "e20550 Background: Smad4 is a tumor suppressor that transduces transforming growth factor beta signaling and regulates genomic stability. We previously found that reduced Smad4 expression was associated with increased DNA damage in both human NSCLC and murine NSCLC models and that reduced Smad4 expression inhibits DNA repair and increases sensitivity to DNA topoisomerase inhibitors. In this study, we assessed the association between reduced Smad4 expression and DNA topoisomerase inhibitor sensitivity in human NSCLC as well as the relationship between Smad4 mutation and homozygous deletion and molecular alterations in other DNA repair molecules. Methods: After IRB approval, we retrospectively identified NSCLC patients who received etoposide or gemcitabine and had an evaluable tumor on CT scan at the University of Colorado Hospital between 2004 to 2014. Chemotherapeutic response was quantified by RECIST criteria, while Smad4 expression was assessed by immunohistochemistry (IHC) and quantified on a 0-300 scale. The relationship between Smad4 mutation and other DNA repair molecule alterations was assessed using TCGA data via cBioPortal. Results: Of the 21 evaluable patients, 19/21 received gemcitabine or etoposide for advanced (stage 3 or 4) disease and 10/21 received these agents with concurrent radiation therapy. Reduced Smad4 expression (IHC score < 100) occurred in 8/21 patients and was associated with non-significant trend (p = 0.18, fisher exact test) toward responsiveness to gemcitabine or etoposide. TCGA data analysis revealed that while Smad4 mutation or homozygous loss was not associated with reduced survival, Smad4 alterations were mutually exclusive to defects in DNA repair molecules. Conclusions: Reduced Smad4 expression may be a biomarker for responsiveness to treatment with chemotherapeutic drugs that inhibit DNA topoisomerase, though this study was underpowered to detect this. That Smad4 signaling alterations are mutually exclusive with alterations in other DNA repair machinery is consistent with a role of Smad4 in regulating DNA repair." @default.
- W2891208504 created "2018-09-27" @default.
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- W2891208504 date "2017-05-20" @default.
- W2891208504 modified "2023-10-14" @default.
- W2891208504 title "Smad4 expression and chemosensitivity in non-small cell lung cancer." @default.
- W2891208504 doi "https://doi.org/10.1200/jco.2017.35.15_suppl.e20550" @default.
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