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

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