Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer

Reddy, Sangeetha M.; Kopetz, Scott; Morris, Jeffrey S.; Parikh, Nila U.; Qiao, Wei; Overman, Michael J.; Fogelman, David R.; Shureiqi, Imad; Jacobs, Carmen; Malik, Zafar; Jiménez, Camilo; Wolff, Robert A.; Abbruzzese, J. L.; Gallick, Gary E.; Eng, Cathy

doi:10.1007/s10637-015-0257-z

Cited by 39 publications

(25 citation statements)

References 37 publications

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“…might inhibit other kinases in addition to Src, such as Lck, c-YES, Lyn, Fyn, Fgr and Blk. It has been shown that AZD0530 effectively reduces Src kinase activity in non-small cell lung cancer and colorectal cancer (Chua et al, 2015;Reddy et al, 2015). Moreover, our screening results in Figure 3A showed that only Src and Tnk2, but not other tyrosine kinases (Lck, c-YES, Lyn, Fyn, Fgr and Blk), functioned as the possible upstream kinases of pY433-MST1.…”

Section: Discussionmentioning

confidence: 77%

Hippo/MST1 signaling mediates microglial activation following acute cerebral ischemia–reperfusion injury

Zhao

Yin

Zhou

et al. 2016

Brain, Behavior, and Immunity

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Cerebral ischemia-reperfusion injury is a major public health concern that causes high rates of disability and mortality in adults. Microglial activation plays a crucial role in ischemic stroke-induced alteration of the immune microenvironment. However, the mechanism underlying the triggering of microglial activation by ischemic stroke remains to be elucidated. Previously, we demonstrated that the protein kinase Hippo/MST1 plays an important role in oxidative stress-induced cell death in mammalian primary neurons and that the protein kinase c-Abl phosphorylates MST1 at Y433, which increases MST1 kinase activity. Microglial activation has been implicated as a secondary detrimental cellular response that contributes to neuronal cell death in ischemic stroke. Here, we are the first, to our knowledge, to demonstrate that MST1 mediates stroke-induced microglial activation by directly phosphorylating IκBα at residues S32 and S36. We further demonstrate that Src kinase functions upstream of MST1-IκB signaling during microglial activation. Specific deletion of MST1 in microglia mitigates stroke-induced brain injury. Therefore, we propose that Src-MST1-IκB signaling plays a critical role in stroke-induced microglial activation. Together with our previous work demonstrating that MST1 is important for oxidative stress-induced neuronal cell death, our results indicate that MST1 could represent a potent therapeutic target for ischemic stroke.

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Section: Discussionmentioning

confidence: 77%

Hippo/MST1 signaling mediates microglial activation following acute cerebral ischemia–reperfusion injury

Zhao

Yin

Zhou

et al. 2016

Brain, Behavior, and Immunity

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“…Its activity results in inhibition of cell proliferation (causing G 0 /G 1 arrest), as well as inhibition of cell adhesion, migration, invasion and tumour metastasis [44,53, [139][140][141][142][143]. Despite the encouraging clinical results for the use of dasatinib as a standalone therapy in CML, clinical findings with dasatinib or alternative Src/ABLkinase inhibitors (saracatinib, bosutinib) [145,146] in PDAC were predominately negative, partially due to poor drug tolerance, but also due to the highly aggressive and adaptable nature of this disease to singleagent targeted therapies and rapid onset of resistance [53,138,[147][148][149][150][151][152][153][154][155][156]. Despite the encouraging clinical results for the use of dasatinib as a standalone therapy in CML, clinical findings with dasatinib or alternative Src/ABLkinase inhibitors (saracatinib, bosutinib) [145,146] in PDAC were predominately negative, partially due to poor drug tolerance, but also due to the highly aggressive and adaptable nature of this disease to singleagent targeted therapies and rapid onset of resistance [53,138,[147][148][149][150][151][152][153][154][155][156].…”

Section: Targeting Src Kinase In Pancreatic Cancermentioning

confidence: 99%

“…These results were particularly promising in models of advanced PDAC, presenting dasatinib as an encouraging antimetastatic agent for this disease [29,56,144]. Despite the encouraging clinical results for the use of dasatinib as a standalone therapy in CML, clinical findings with dasatinib or alternative Src/ABLkinase inhibitors (saracatinib, bosutinib) [145,146] in PDAC were predominately negative, partially due to poor drug tolerance, but also due to the highly aggressive and adaptable nature of this disease to singleagent targeted therapies and rapid onset of resistance [53,138,[147][148][149][150][151][152][153][154][155][156]. Moreover, the presumption that these biologic agents would significantly improve survival in nonstratified cohorts, particularly in PDAC, is inconsistent with prior preclinical data, which suggests that therapeutic response may correlate with biological markers.…”

Section: Targeting Src Kinase In Pancreatic Cancermentioning

confidence: 99%

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

et al. 2019

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Pancreatic cancer, a disease with extremely poor prognosis, has been notoriously resistant to virtually all forms of treatment. The dynamic crosstalk that occurs between tumour cells and the surrounding stroma, frequently mediated by intricate Src/FAK signalling, is increasingly recognised as a key player in pancreatic tumourigenesis, disease progression and therapeutic resistance. These important cues are fundamental for defining the invasive potential of pancreatic tumours, and several components of the Src and downstream effector signalling have been proposed as potent anticancer therapeutic targets. Consequently, numerous agents that block this complex network are being extensively investigated as potential antiinvasive and antimetastatic therapeutic agents for this disease. In this review, we will discuss the latest evidence of Src signalling in PDAC progression, fibrotic response and resistance to therapy. We will examine future opportunities for the development and implementation of more effective combination regimens, targeting key components of the oncogenic Src signalling axis, and in the context of a precision medicine‐guided approach.

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“…However, at 2 μ mol/L saracatinib, which effectively inhibited SFK and ABCB1 activities in VR cells, the drug concentration was remarkably higher than the serum concentration in patients from a previous study who took once‐daily 175‐mg doses of saracatinib . This finding may be a causative factor in the negative clinical trial results for NSCLC and other malignancies .…”

Section: Discussionmentioning

confidence: 80%

The synergistic role of ATP‐dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer

et al. 2018

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The vinorelbine (VRB) plus cisplatin regimen is widely used to treat non–small cell lung cancer (NSCLC), but its cure rate is poor. Drug resistance is the primary driver of chemotherapeutic failure, and the causes of resistance remain unclear. By focusing on the focal adhesion (FA) pathway, we have highlighted a signaling pathway that promotes VRB resistance in lung cancer cells. First, we established VRB‐resistant (VR) lung cancer cells (NCI‐H1299 and A549) and examined its transcriptional changes, protein expressions, and activations. We treated VR cells by Src Family Kinase (SFK) inhibitors or gene silencing and examined cell viabilities. ATP‐binding Cassette Sub‐family B Member 1 (ABCB1) was highly expressed in VR cells. A pathway analysis and western blot analysis revealed the high expression of integrins β1 and β3 and the activation of FA pathway components, including Src family kinase (SFK) and AKT, in VR cells. SFK involvement in VRB resistance was confirmed by the recovery of VRB sensitivity in FYN knockdown A549 VR cells. Saracatinib, a dual inhibitor of SFK and ABCB1, had a synergistic effect with VRB in VR cells. In conclusion, ABCB1 is the primary cause of VRB resistance. Additionally, the FA pathway, particularly integrin, and SFK, are promising targets for VRB‐resistant lung cancer. Further studies are needed to identify clinically applicable target drugs and biomarkers that will improve disease prognoses and predict therapeutic efficacies.

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Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer

Abstract: Saracatinib is a novel oral Src kinase inhibitor that was well tolerated but failed to meet its primary endpoint of improvement in 4 month progression-free survival as a single agent in previously treated metastatic colorectal cancer patients.

Cited by 39 publications

References 37 publications

Hippo/MST1 signaling mediates microglial activation following acute cerebral ischemia–reperfusion injury

Hippo/MST1 signaling mediates microglial activation following acute cerebral ischemia–reperfusion injury

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

The synergistic role of ATP‐dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer

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