Abstract | OBJECTIVE: MATERIALS AND METHODS: We retrospectively identified NSCLC patients who received etoposide or gemcitabine. Chemotherapeutic response was quantified by RECIST 1.1 criteria and Smad4 expression was assessed by immunohistochemistry. Relationships between Smad4 mutation and DNA repair molecule mutations were evaluated using publically available datasets. RESULTS: We identified 28 individuals who received 30 treatments with gemcitabine or etoposide containing regimens for NSCLC. Reduced Smad4 expression was seen in 13/28 patients and was not associated with significant differences in clinical or pathologic parameters. Patients with reduced Smad4 expression had a larger response to DNA topoisomerase inhibitor containing regimens then patients with high Smad4 expression (-25.7% vs. -6.8% in lesion size, p=0.03); this relationship was more pronounced with gemcitabine containing regimens. The overall treatment response was higher in patients with reduced Smad4 expression (8/14 vs 2/16 p=0.02). Analysis of data from The Cancer Genome Atlas revealed that Smad4 mutation or homozygous loss was mutually exclusive with genomic alterations in DNA repair molecules. CONCLUSIONS: Reduced Smad4 expression may predict responsiveness to regimens that contain DNA topoisomerase inhibitors. That Smad4 signaling alterations are mutually exclusive with alterations in DNA repair machinery is consistent with an important role of Smad4 in regulating DNA repair.
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Authors | Michael Ziemke, Tejas Patil, Kyle Nolan, Darinee Tippimanchai, Stephen P Malkoski |
Journal | Lung cancer (Amsterdam, Netherlands)
(Lung Cancer)
Vol. 109
Pg. 28-35
(07 2017)
ISSN: 1872-8332 [Electronic] Ireland |
PMID | 28577946
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2017 Elsevier B.V. All rights reserved. |
Chemical References |
- Biomarkers, Pharmacological
- SMAD4 protein, human
- Smad4 Protein
- Topoisomerase I Inhibitors
- Transforming Growth Factor beta
- Deoxycytidine
- Etoposide
- Gemcitabine
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Topics |
- Aged
- Antineoplastic Combined Chemotherapy Protocols
(therapeutic use)
- Biomarkers, Pharmacological
(metabolism)
- Carcinoma, Non-Small-Cell Lung
(drug therapy, genetics)
- DNA Repair
(genetics)
- Deoxycytidine
(analogs & derivatives, therapeutic use)
- Down-Regulation
- Drug Resistance, Neoplasm
- Etoposide
(therapeutic use)
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Lung Neoplasms
(drug therapy, genetics)
- Male
- Middle Aged
- Retrospective Studies
- Signal Transduction
- Smad4 Protein
(genetics, metabolism)
- Topoisomerase I Inhibitors
(therapeutic use)
- Transforming Growth Factor beta
(metabolism)
- Gemcitabine
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