<scp>AZD</scp>0530 sensitizes drug‐resistant<scp>ALK</scp>‐positive lung cancer cells by inhibiting<scp>SRC</scp>signaling

Zhao, Yi; Yang, Yi; Xu, Yunhua; Lü, Shun; Hong, Jian

doi:10.1002/2211-5463.12162

Cited by 14 publications

(9 citation statements)

References 20 publications

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“…For example, AXL , a druggable kinase implicated as a resistance driver for many targeted therapies (Liu et al, 2009; Zhang et al, 2012), has significant negative CARE scores for multiple compounds screened in three cohorts (Figure 2A, B). Another example is that SRC has negative CARE scores on most drugs (Figure 2A, C), which corroborates previous findings that SRC activation promotes resistance towards several targeted therapies (Wilson et al, 2014; Zhao et al, 2017). In contrast, CSK , a negative regulator of SRC (Okada et al, 1991), has significant positive CARE scores for many compounds (Figure 2C), suggesting that loss of CSK may promote drug resistance towards many targeted therapies.…”

Section: Resultssupporting

confidence: 89%

Genome-Scale Signatures of Gene Interaction from Compound Screens Predict Clinical Efficacy of Targeted Cancer Therapies

Jiang

Lee

et al. 2018

Cell Systems

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Identifying reliable drug response biomarkers is a significant challenge in cancer research. We present computational analysis of resistance (CARE), a computational method focused on targeted therapies, to infer genome-wide transcriptomic signatures of drug efficacy from cell line compound screens. CARE outputs genome-scale scores to measure how the drug target gene interacts with other genes to affect the inhibitor efficacy in the compound screens. Such statistical interactions between drug targets and other genes were not considered in previous studies but are critical in identifying predictive biomarkers. When evaluated using transcriptome data from clinical studies, CARE can predict the therapy outcome better than signatures from other computational methods and genomics experiments. Moreover, the CARE signatures for the PLX4720 BRAF inhibitor are associated with an anti-programmed death 1 clinical response, suggesting a common efficacy signature between a targeted therapy and immunotherapy. When searching for genes related to lapatinib resistance, CARE identified PRKD3 as the top candidate. PRKD3 inhibition, by both small interfering RNA and compounds, significantly sensitized breast cancer cells to lapatinib. Thus, CARE should enable large-scale inference of response biomarkers and drug combinations for targeted therapies using compound screen data.

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Section: Resultssupporting

confidence: 89%

Genome-Scale Signatures of Gene Interaction from Compound Screens Predict Clinical Efficacy of Targeted Cancer Therapies

Jiang

Lee

et al. 2018

Cell Systems

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“…Masitinib, another SFK tyrosine kinase inhibitor, was assessed in a randomized controlled open-label trail, and showed that masitinib generated a statistically signi cant survival bene t over standard of care in advanced gastrointestinal stromal tumor [30]. Saracatinib (AZD0530) targets Fyn and inhibits the growth of lung cancer cells that are resistant to ALK inhibitors [31], interestingly, this compound also suppresses Fyn induced invasion and metastasis by decreasing Vimentin and Snail [32]. However, subsequent studies showed that saracatinib inhibits other SFKs kinase activities, such as Src, Yes, and Lyn.…”

Section: Discussionmentioning

confidence: 99%

A Novel Chalcone derivative suppresses Melanoma cell growth through targeting Fyn/Stat3 pathway

Tang

Long

et al. 2020

Preprint

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Background: Fyn has been documented to have oncogenic features in multiple tumors, which might be a potential therapeutic target, however, few studies on the function role of Fyn and its specific inhibitors in melanoma. Methods: We investigated the impacts of Fyn and its inhibitor Lj-1-60 on melanoma through bioinformatics analysis, western blot, cell viability, cell cycle and apoptosis and xenograft tumor model as well as immunohistochemical staining. Pull-down and in vitro kinase assay were used to demonstrate Lj-1-60 targeting Fyn. Transcriptome sequencing and RT-PCR were adopted to confirm the potential mechanisms of Lj-1-60 in melanoma. Results: Our findings showed that Fyn was overexpressed in melanoma cells and knocked down of Fyn suppressed the proliferation of melanoma cells. To identify the potential inhibitors of Fyn, our in-house library including total of 111277 chemicals was conducted to vitro screening, among those compounds, 83 inhibitors were further detected to explore the effect on melanoma cells growth and discovered a novel chalcone derivative Lj-1-60 that exhibited low cellular toxicity and high anti-tumor efficacy. Lj-1-60 directly was associated with Fyn and inhibited the Fyn kinase activity with Stat3 as substrate. What’s more, Lj-1-60 suppressed the proliferation of melanoma in vitro and in vivo through inducing cell cycle arrest and apoptosis. Moreover, the activation of Stat3 had also been abrogated both in Lj-1-60 treated melanoma cells or Fyn knocked down cells. Conclusion: Our study revealed a novel Fyn inhibitor that could significantly suppress melanoma growth, which is a promising potential inhibitor for melanoma treatment.

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“…Masitinib, another SFK tyrosine kinase inhibitor, was assessed in a small phase II clinical trial for AD, ameliorated cognitive function and activities of daily living [28]. Saracatinib (AZD0530) targets Fyn and inhibits the growth of lung cancer cells that are resistant to ALK inhibitors [29], interestingly, this compound also suppresses Fyn induced invasion and metastasis by decreasing Vimentin and Snail [30]. However, subsequent studies showed that saracatinib inhibits other SFKs kinase activities, such as Src, Yes, and Lyn.…”

Section: Discussionmentioning

confidence: 99%

A Novel Chalcone derivative suppresses Melanoma cell growth through targeting Fyn/Stat3 pathway

Tang

Long

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Fyn has been documented to have oncogenic features in multiple tumors, which might be a potential therapeutic target, however, few studies on the function role of Fyn and its specific inhibitors in melanoma.Methods: We investigated the impacts of Fyn and its inhibitors Lj-1-60 on melanoma by way of bioinformatics analysis, western blot, cell viability, cell cycle and apoptosis and xenograft tumor model as well as immunohistochemical staining. Pull-down and in vitro phosphorylation assay to further demonstrate Lj-1-60 targeting Fyn. Transcriptome sequencing and RT-PCR to confirm the potential mechanisms of Lj-1-60 in melanoma.Results: Our findings showed that Fyn is overexpressed in melanoma cells and knock down of Fyn suppresses the proliferation of melanoma cells. To identify the potential inhibitors of Fyn, our in-house library including total of 11277 chemicals was conducted to vitro screening, among those compounds, eighty-three inhibitors were further detected to explore the effect on melanoma cells growth and discovered a novel chalcone derivative Lj-1-60 exhibited low cellular toxicity and high anti-tumor efficacy. Lj-1-60 directly associates with Fyn and inhibits the Fyn kinase activity with Stat3 as substrate. What’s more, Lj-1-60 suppresses the proliferation of melanoma in vitro and in vivo through inducing cell cycle arrest and apoptosis. Moreover, the activation of Stat3 had also been abrogated both in Lj-1-60 treated melanoma cells or Fyn knocking down cells.Conclusion: Our study revealed a novel Fyn inhibitor could significantly suppress melanoma growth, which is a promising potential inhibitor for melanoma treatment.

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AZD0530 sensitizes drug‐resistantALK‐positive lung cancer cells by inhibitingSRCsignaling

Cited by 14 publications

References 20 publications

Genome-Scale Signatures of Gene Interaction from Compound Screens Predict Clinical Efficacy of Targeted Cancer Therapies

Genome-Scale Signatures of Gene Interaction from Compound Screens Predict Clinical Efficacy of Targeted Cancer Therapies

A Novel Chalcone derivative suppresses Melanoma cell growth through targeting Fyn/Stat3 pathway

A Novel Chalcone derivative suppresses Melanoma cell growth through targeting Fyn/Stat3 pathway

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