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Smad4 loss promotes lung cancer formation but increases sensitivity to DNA topoisomerase inhibitors

Oncogene volume 35, pages 577–586 (2016)Cite this article

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Abstract

Non-small-cell lung cancer (NSCLC) is a common malignancy with a poor prognosis. Despite progress targeting oncogenic drivers, there are no therapies targeting tumor-suppressor loss. Smad4 is an established tumor suppressor in pancreatic and colon cancer; however, the consequences of Smad4 loss in lung cancer are largely unknown. We evaluated Smad4 expression in human NSCLC samples and examined Smad4 alterations in large NSCLC data sets and found that reduced Smad4 expression is common in human NSCLC and occurs through a variety of mechanisms, including mutation, homozygous deletion and heterozygous loss. We modeled Smad4 loss in lung cancer by deleting Smad4 in airway epithelial cells and found that Smad4 deletion both initiates and promotes lung tumor development. Interestingly, both Smad4−/− mouse tumors and human NSCLC samples with reduced Smad4 expression demonstrated increased DNA damage, whereas Smad4 knockdown in lung cancer cells reduced DNA repair and increased apoptosis after DNA damage. In addition, Smad4-deficient NSCLC cells demonstrated increased sensitivity to both chemotherapeutics that inhibit DNA topoisomerase and drugs that block double-strand DNA break repair by non-homologous end joining. In sum, these studies establish Smad4 as a lung tumor suppressor and suggest that the defective DNA repair phenotype of Smad4-deficient tumors can be exploited by specific therapeutic strategies.

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Acknowledgements

This work was supported by the NIH/NCI (K08 CA131483 to SPM) and NIH/NIDCR (R01 DE015953 to XJW). SPM was also supported by the National Lung Cancer Partnership and a Career Development Award from the Colorado Lung Cancer SPORE (P50 CA058187) and an American Cancer Society Institutional Research Grant (ACS IRG 57-001-53). The OHSU BioLibrary is supported by P30 CA069533. The Colorado Lung Cancer SPORE Tissue Bank is supported by P30 CA046934 and P50 CA058187. We thank OHSU BioLibrary staff for their assistance with patient samples. We also thank Jerry Haney, Christina Nall, Marina Lewis and Wilbur Franklin at the Colorado Lung SPORE for assistance acquiring patient samples and data.

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Author notes

  1. S M Haeger and J J Thompson: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA

    S M Haeger, J J Thompson, S Kalra, T G Cleaver & S P Malkoski

  2. Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA

    D Merrick, X-J Wang & S P Malkoski

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  1. S M Haeger
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Correspondence to S P Malkoski.

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Competing interests

This work has been funded by the NIH (to Drs Malkoski and Wang), the National Lung Cancer Partnership (to Dr Malkoski) and the American Cancer Society (to Dr Malkoski). The remaining authors declare no conflict of interest.

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Haeger, S., Thompson, J., Kalra, S. et al. Smad4 loss promotes lung cancer formation but increases sensitivity to DNA topoisomerase inhibitors. Oncogene 35, 577–586 (2016). https://doi.org/10.1038/onc.2015.112

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