Response to dasatinib in a patient with SQCC of the lung harboring a discoid-receptor-2 and synchronous chronic myelogenous leukemia

Pitini, Vincenzo; Arrigo, Carmela; Mirto, Cristian Di; Mondello, Patrizia; Altavilla, Giuseppe

doi:10.1016/j.lungcan.2013.07.004

Cited by 55 publications

(42 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, a patient with lung SCC who harboured a DDR2 kinase mutation, but did not have any EGF receptor mutations, responded to a combination of dasatinib and erlotinib (an inhibitor of EGF receptor) treatment, which provided a rationale for clinical use of DDR2 kinase inhibitors [116]. This is backed up by another report on a lung SCC patient who responded to dasatinib treatment and was found to have the same DDR2 kinase mutation [121]. The initial study concluded that gain of functions mutations in DDR2 are oncogenic and provided the first targetable mutations in lung SCC [116] and hence caused much excitement in the field.…”

Section: Ddrs and Cancermentioning

confidence: 99%

Extracellular matrix component signaling in cancer

Multhaupt

Leitinger

Gullberg

et al. 2016

Advanced Drug Delivery Reviews

160

109

View full text Add to dashboard Cite

Section: Ddrs and Cancermentioning

confidence: 99%

Extracellular matrix component signaling in cancer

Multhaupt

Leitinger

Gullberg

et al. 2016

Advanced Drug Delivery Reviews

160

109

View full text Add to dashboard Cite

“…The clinical activity of dasatinib in lung cancer is being evaluated in a number of clinical trials (12, 13). Of note, a recent case report provided further evidence of clinical activity of dasatinib in a patient with lung SCC harboring DDR2 mutation (14). …”

Section: Introductionmentioning

confidence: 99%

Adaptive Responses to Dasatinib-Treated Lung Squamous Cell Cancer Cells Harboring DDR2 Mutations

et al. 2014

View full text Add to dashboard Cite

DDR2 mutations occur in ~4% of lung squamous cell cancer (SCC) where the tyrosine kinase inhibitor dasatinib has emerged as a new therapeutic option. We found that ERK and AKT phosphorylation was weakly inhibited by dasatinib in DDR2-mutant lung SCC cells, suggesting that dasatinib inhibits survival signals distinct from other oncogenic RTKs and/or compensatory signals exist that dampen dasatinib activity. To gain better insight into dasatinib’s action in these cells, we assessed altered global tyrosine phosphorylation (pY) after dasatinib exposure, employing a mass spectrometry (MS)-based quantitative phosphoproteomics approach. Overlaying protein-protein interaction relationships upon this dasatinib-regulated pY network revealed decreased phosphorylation of Src family kinases and their targets. Conversely, dasatinib enhanced tyrosine phosphorylation in a panel of receptor tyrosine kinases (RTK) and their signaling adaptor complexes, including EGFR, MET/GAB1, and IGF-1R/IRS2, implicating a RTK-driven adaptive response associated with dasatinib. To address the significance of this observation, these results were further integrated with results from a small molecule chemical library screen. We found that dasatinib combined with MET and IGF-1R inhibitors had a synergistic effect and ligand stimulation of EGFR and MET rescued DDR2-mutant lung SCC cells from dasatinib-induced loss of cell viability. Importantly, we observed high levels of tyrosine-phosphorylated EGFR and MET in a panel of human lung SCC tissues harboring DDR2 mutations. Our results highlight potential RTK-driven adaptive resistant mechanisms upon DDR2 targeting, and they suggest new, rationale co-targeting strategies for DDR2-mutant lung SCC.

show abstract

“…25 Two recent clinical studies demonstrated that the lung cancer patients who carry oncogenic mutations of DDR2 showed response to dasatinib treatment. 29,30 The only in vivo evidence for a role of DDR2 in fibrotic disease showed that DDR2 knockout mice exhibited exaggerated severity of chronic hepatic fibrosis. 31 Although a previous in vitro study has demonstrated that DDR2 promotes lung fibroblast proliferation and migration, 32 till now it remains unclear whether and how DDR2 contributes to the pathogenesis of pulmonary fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Targeting of Discoidin Domain Receptor 2 (DDR2) Prevents Myofibroblast Activation and Neovessel Formation During Pulmonary Fibrosis

Zhao

Bian

et al. 2016

Molecular Therapy

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) is a lethal human disease with short survival time and few treatment options. Herein, we demonstrated that discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase that predominantly transduces signals from fibrillar collagens, plays a critical role in the induction of fibrosis and angiogenesis in the lung. In vitro cell studies showed that DDR2 can synergize the actions of both transforming growth factor (TGF)-β and fibrillar collagen to stimulate lung fibroblasts to undergo myofibroblastic changes and vascular endothelial growth factor (VEGF) expression. In addition, we confirmed that late treatment of the injured mice with specific siRNA against DDR2 or its kinase inhibitor exhibited therapeutic efficacy against lung fibrosis. Thus, this study not only elucidated novel mechanisms by which DDR2 controls the development of pulmonary fibrosis, but also provided candidate target for the intervention of this stubborn disease.

show abstract

Response to dasatinib in a patient with SQCC of the lung harboring a discoid-receptor-2 and synchronous chronic myelogenous leukemia

Cited by 55 publications

References 6 publications

Extracellular matrix component signaling in cancer

Extracellular matrix component signaling in cancer

Adaptive Responses to Dasatinib-Treated Lung Squamous Cell Cancer Cells Harboring DDR2 Mutations

Targeting of Discoidin Domain Receptor 2 (DDR2) Prevents Myofibroblast Activation and Neovessel Formation During Pulmonary Fibrosis

Contact Info

Product

Resources

About