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.
Highlights
Lung cancer is the second most common cancer and accounts for about 15% of all cancer diagnoses
Song et al demonstrated that dasatinib induces apoptosis in a number of non-small cell lung cancer (NSCLC) cells that exhibit a mutant epidermal growth factor receptor (EGFR) phenotype; this effect was not observed in NSCLC cell lines with a wild-type EGFR phenotype [9]
We found that dasatinib treatment alone had very little effect; when NSCLC cell lines were treated with a combination of Transforming growth factor b (TGFb) and dasatinib, apoptosis was induced
Summary
Lung cancer is the second most common cancer and accounts for about 15% of all cancer diagnoses. Alternate therapies are urgently needed for patients with EGFR mutations who initially respond to EGFR TKIs therapies but eventually develop resistance, as well as for patients who exhibit the wild-type EGFR genotype [1]. This resistance could be partly because of the complexity that characterizes the signaling of these types of proteins as well as the heterogeneity of lung adenocarcinomas [2]. Clinical trials have tested the efficacy of dasatinib in NSCLC as a single agent [6], in combination with currently used chemotherapy regimens such as the epidermal growth factor receptor (EGFR) inhibitor erlotinib [7], and in patients who have developed resistance to erlotinib and gefitinib [8]. Song et al demonstrated that dasatinib induces apoptosis in a number of NSCLC cells that exhibit a mutant EGFR phenotype; this effect was not observed in NSCLC cell lines with a wild-type EGFR phenotype [9]
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