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.

Differential effects of sevoflurane on the metastatic potential and chemosensitivity of non-small-cell lung adenocarcinoma and renal cell carcinoma in vitro

“…This is supported by a recent studies showing inhibition of the non-Smad pathway components p38 MAPK, 21 Akt, 23 and ERK 24 by sevoflurane in lung. Gordian and colleagues 25 found exogenous TGF-b1 enhances the chemosensitivity of A549. However other studies have found that TGF-b/Smad promotes cell invasion and epithelial-mesenchymal transition in NSCLC, 26 and Smad activation correlates with poor prognosis in ADC.…”

Dasatinib blocks transcriptional and promigratory responses to transforming growth factor-beta in pancreatic adenocarcinoma cells through inhibition of Smad signalling: implications for in vivo mode of action

“…Later, this observation was confirmed in docking studies using the previously reported crystal structure of the ALK5 cytoplasmic domain. Here, the binding of dasatinib to ALK5 presented with the highest score when compared to the structurally related bosutinib, the commercially available ALK5 inhibitor LY-364947, and dorsomorphin [ 25 ].…”

“…Gordian and colleagues [ 25 ] studied the combined effects of dasatinib and TGF-β on A549 NSCLC cells. When combined with TGF-β1 stimulation, dasatinib induced apoptosis in EGF-R mutant cells along with upregulation of pro-apoptotic BIM protein.…”

“…Like SRC, TGF-β/ALK5 signalling is currently targeted in the experimental and clinical treatment of various tumours. Given i) the interaction of dasatinib with ALK5 [ 18 , 25 ], ii) the structural similarity of dasatinib with the experimental SRC inhibitors PP2 and PP1, and iii) the ability of PP2 and PP1 to effectively inhibit the ALK5 kinase activity as well as TGF-β1-induced prooncogenic responses [ 26 , 27 ], we hypothesized that dasatinib should be able to block TGF-β1 signalling towards migratory, invasive and prometastatic outcomes. That dasatinib may possess potential efficacy against profibrotic TGF-β signalling in vivo was suggested by preclinical studies, in which dasatinib treatment of scleroderma and normal fibroblasts led to decreased production of extracellular matrix proteins [ 28 ].…”

Mechanism Comparison of Gemcitabine and Dasatinib-Resistant Pancreatic Cancer by Integrating mRNA and miRNA Expression Profiles

“…Gordian et al reported that transforming growth factor beta signaling overcomes dasatinib resistance in lung cancer [29]. Beauchamp et al demonstrated that DDR2 gatekeeper mutation and bypass pathway activated by NF1 loss conferred resistance to dasatinib in lung cancer cell lines [30]. In line with lung cancer, mitogen-activated protein kinase pathway facilitates resistance to the src inhibitor dasatinib in thyroid cancer [31].…”