title: Transforming growth factor β signaling overcomes dasatinib resistance in lung cancer.
abstract: Lung cancer is the second most common cancer and the leading cause of cancer-related deaths. Despite recent advances in the development of targeted therapies, patients with advanced disease remain incurable, mostly because metastatic non-small cell lung carcinomas (NSCLC) eventually become resistant to tyrosine kinase inhibitors (TKIs). Kinase inhibitors have the potential for target promiscuity because the kinase super family is the largest family of druggable genes that binds to a common substrate (ATP). As a result, TKIs often developed for a specific purpose have been found to act on other targets. Drug affinity chromatography has been used to show that dasatinib interacts with the TGFβ type I receptor (TβR-I), a serine-threonine kinase. To determine the potential biological relevance of this association, we studied the combined effects of dasatinib and TGFβ on lung cancer cell lines. We found that dasatinib treatment alone had very little effect; however, when NSCLC cell lines were treated with a combination of TGFβ and dasatinib, apoptosis was induced. Combined TGFβ-1 + dasatinib treatment had no effect on the activity of Smad2 or other non-canonical TGFβ intracellular mediators. Interestingly, combined TGFβ and dasatinib treatment resulted in a transient increase in p-Smad3 (seen after 3 hours). In addition, when NSCLC cells were treated with this combination, the pro-apoptotic protein BIM was up-regulated. Knockdown of the expression of Smad3 using Smad3 siRNA also resulted in a decrease in BIM protein, suggesting that TGFβ-1 + dasatinib-induced apoptosis is mediated by Smad3 regulation of BIM. Dasatinib is only effective in killing EGFR mutant cells, which is shown in only 10% of NSCLCs. Therefore, the observation that wild-type EGFR lung cancers can be manipulated to render them sensitive to killing by dasatinib could have important implications for devising innovative and potentially more efficacious treatment strategies for this disease.
authors.affiliation: Molecular Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, United States of America.
authors.forename: Edna
authors.initials: E
authors.lastname: Gordian
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, United States of America.
authors.forename: Jiannong
authors.initials: J
authors.lastname: Li
authors.affiliation: Chemical Biology Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, United States of America.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Pevzner
authors.affiliation: Immunology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, United States of America.
authors.forename: Melanie
authors.initials: M
authors.lastname: Mediavilla-Varela
authors.affiliation: Cancer Imaging & Metabolism Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, United States of America.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Luddy
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, United States of America.
authors.forename: Kim
authors.initials: K
authors.lastname: Ohaegbulam
authors.affiliation: Chemical Biology Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, United States of America.
authors.forename: Kenyon G
authors.initials: KG
authors.lastname: Daniel
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, United States of America.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
authors.affiliation: Molecular Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, United States of America.
authors.forename: Teresita
authors.initials: T
authors.lastname: Muñoz-Antonia
mesh_terms: D000814:Aniline Compounds / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D045744:Cell Line, Tumor; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology*; D062105:Molecular Docking Simulation; D009570:Nitriles / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051900:Smad3 Protein / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009570:Nitriles; D011743:Pyrimidines; D011804:Quinolines; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; D013844:Thiazoles; D016212:Transforming Growth Factor beta; C471992:bosutinib; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000069439:Dasatinib