Acquired Resistance to EGFR TKIs Mediated by TGFβ1/Integrin β3 Signaling in EGFR-Mutant Lung Cancer

Wang, Caiyun; Wang, Tao; Lv, Dacheng; Li, Ling; Yue, Jinnan; Chen, Hong Zhuan; Xu, Lu

doi:10.1158/1535-7163.mct-19-0181

Cited by 32 publications

(34 citation statements)

References 29 publications

(46 reference statements)

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“…Integrin αVβ3 expression and activation drive the intracellular signalling that promotes cancer cell survival, invasion, metastasis, angiogenesis, and self-renewal [39,41], as well as chemotherapy resistance [42,43] and radiotherapy resistance [44,45]. Several studies have reported that integrin β3 is up-regulated after EGFR-TKI treatment [46,47], consistent with our findings. More importantly, our findings add to current knowledge about how integrin β3 is upregulated in resistant tumours.…”

Section: Discussionsupporting

confidence: 90%

“…Overexpression of OPN/integrin αvβ3 results in activation of downstream FAK signalling, which is a key component of the signal transduction pathways activated by integrins and has an essential role in cancer cell survival, EMT, metastasis, and stemness [49]. Several studies have shown that activation of FAK signalling is associated with EGFR-TKI resistance [46,47]. Based on our results, VS-6063 can enhance sensitivity to gefitinib in PC9GR cells.…”

Section: Discussionsupporting

confidence: 59%

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Abnormally activated OPN/integrin αVβ3/FAK signalling is responsible for EGFR-TKI resistance in EGFR mutant non-small-cell lung cancer

Zhang

et al. 2020

J Hematol Oncol

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Background Acquired epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance limits the long-term clinical efficacy of tyrosine kinase-targeting drugs. Although most of the mechanisms of acquired EGFR-TKI resistance have been revealed, the mechanism of ~ 15% of cases has not yet been elucidated. Methods Cell viability was analysed using the Cell Counting Kit-8 (CCK-8) assay. Proteome profiler array analysis was performed to find proteins contributing to acquired EGFR-TKI resistance. Secreted OPN was detected by ELISA. Immunohistochemical analysis was conducted to detect expression of integrin αV in NSCLC tissue. The effect of VS-6063 on apoptosis and proliferation of PC9 gefitinib-resistant cells was detected by fluorescence-activated cell sorting (FACS) and clonogenic assays. A mouse xenograft model was used to assess the effect of VS-6063 on the sensitivity of PC9 gefitinib-resistant cells to gefitinib. Results OPN was overexpressed in acquired EGFR-TKI-resistant NSCLCs. Secreted OPN contributed to acquired EGFR-TKI resistance by activating the integrin αVβ3/FAK pathway. Inhibition of FAK signalling increased sensitivity to EGFR-TKIs in PC9 gefitinib-resistant cells both in vitro and in vivo. Conclusions OPN contributes to acquired EGFR-TKI resistance by up-regulating expression of integrin αVβ3, which activates the downstream FAK/AKT and ERK signalling pathways to promote cell proliferation in NSCLC.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 59%

Abnormally activated OPN/integrin αVβ3/FAK signalling is responsible for EGFR-TKI resistance in EGFR mutant non-small-cell lung cancer

Zhang

et al. 2020

J Hematol Oncol

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“…EGFR-TKIs are the most representative class of targeted therapies. Compared with traditional chemotherapy, EGFR-TKIs effectively treat advanced NSCLC with EGFR mutations and significantly prolong the OS of those patients [23][24][25]. However, the application of EGFR-TKIs also has some certain limitations.…”

Section: Discussionmentioning

confidence: 99%

EZH2 inhibitors reverse resistance to gefitinib in primary EGFR wild-type lung cancer cells

Gong

Yin

et al. 2020

BMC Cancer

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Background Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. In traditional anti-cancer therapy, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) have been proven to be beneficial for patients with EGFR mutations. However, patients with EGFR wild-type NSCLC were usually not respond to EGFR-TKIs. Enhancer of zeste homolog 2 (EZH2) is a key molecular in the PRC2 complex and plays an important role in epigenetic regulation and is overexpressed in variant tumors. EZH2 inhibitors have been reported to sensitize variant tumor cells to anticancer drugs. This study aimed to investigate whether the EZH2 inhibitors, GSK343 and DZNep when combined with gefitinib can reverse EGFR-TKIs resistance in EGFR wild-type NSCLC cells. Methods The RNA-sequencing data of patients with NSCLC [502 patients with lung squamous cell carcinoma, including 49 paracancerous lung tissues and 513 patients with lung adenocarcinoma (LUAD), including 59 paracancerous lung tissues] from the Cancer Genome Atlas (TCGA), were analyzed for EZH2 expression. EZH2 expression was verified in 40 NSCLC tissue cancer samples and their corresponding paracancerous tissues from our institute (TJMUGH) via RT-PCR. A549 and H1299 cells treated with siRNA or EZH2 inhibitors were subjected to cell viability and apoptosis analyses as well to EGFR pathway proteins expression analyses via western blotting. Results EZH2 was upregulated in human NSCLC tissues and correlated with poor prognosis in patients with LUAD based on data from both TCGA and TJMUGH. Both GSK343 and DZNep sensitized EGFR wild-type LUAD cells (A549 and H1299) to gefitinib and suppressed cell viability and proliferation in vitro by downregulating the phosphorylation of EGFR and AKT and by inducing cell apoptosis. Co-administration of EZH2 inhibitors (GSK343 or DZNep) with gefitinib exerted a stronger inhibitory effect on tumor activity, cell proliferation and cell migration than single drug administration in vitro and in vivo. Conclusions These data suggest that the combination of EZH2 inhibitors with EGFR-TKIs may be an effective method for treating NSCLC-patients with EGFR-wild type, who do not want to undergo traditional treatment with chemotherapy.

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“…Tumor recurrence and metastasis present marked challenges to clinicians and severely affect the prognosis of patients. Approximately prolong OS of patients [29][30][31] . However, the application of EGFR-TKIs also has some certain limitations.…”

Section: Discussionmentioning

confidence: 99%

Ezh2 Inhibitors Reverse Resistance to Gefitinib in Primary Egfr Wild-type Lung Cancer Cells

Gong

Yin

et al. 2020

Preprint

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Background: Lung cancer is the leading cause of cancer-related death worldwide. Non–small-cell lung cancer (NSCLC) is the most common type of lung cancer. Traditional anticancer therapies involving epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) have been proven beneficial in the treatment of patients with EGFR mutations. However, patients with EGFR wild-type NSCLC usually fail to respond to EGFR-TKIs. Enhancer of zeste homolog 2 (EZH2), a key molecule of the PRC2 complex, plays an important role in epigenetic regulation and is overexpressed in various tumors. EZH2 inhibitors sensitize various types of tumor cells to antitumor drugs. Therefore, this study aimed to investigate whether the EZH2 inhibitors GSK343 and DZNep, whencombined with gefitinib, can reverse EGFR-TKI resistance in EGFR wild-type NSCLC. Methods:EZH2 expression was evaluated using the RNA sequencing dataset of NSCLC patients (502 lung squamous cell carcinoma cases including 49 paracancerous lung tissues and 513 lung adenocarcinoma cases including 59 paracancerous lung tissues) from The Cancer Genome Atlas (TCGA). We simultaneously also verified EZH2 expressionin 40 NSCLC samples and their corresponding paracancerous lung tissues from our institution via quantitative PCR. The lung adenocarcinoma cell lines A549 and H1299 were treated with EZH2-specific small interfering RNA or EZH2 inhibitors and subjected to analyses of cell viability and apoptosis as well as of EGFR pathway protein expressions by western blotting. Results: EZH2 was upregulated in human NSCLC tissues and was correlated with poor prognosis in patients with lung adenocarcinoma based on data from both TCGA and our institution. Both EZH2 inhibitors sensitized A549 and H1299 cells to gefitinib and suppressed cell viability and proliferation in vitroby downregulating the phosphorylation of EGFR and AKT and inducing cell apoptosis. Co-administration of EZH2 inhibitors (GSK343 or DZNep) with gefitinib exerted stronger inhibitory effects on tumor activity, cell proliferation, and cell migration than single drug administration in vitro and in vivo.Conclusion: Co-administration of EZH2 inhibitors with EGFR-TKIs may be feasible for the treatment of EGFR wild-type NSCLC in patients who refuse traditional chemotherapy.

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Acquired Resistance to EGFR TKIs Mediated by TGFβ1/Integrin β3 Signaling in EGFR-Mutant Lung Cancer

Cited by 32 publications

References 29 publications

Abnormally activated OPN/integrin αVβ3/FAK signalling is responsible for EGFR-TKI resistance in EGFR mutant non-small-cell lung cancer

Abnormally activated OPN/integrin αVβ3/FAK signalling is responsible for EGFR-TKI resistance in EGFR mutant non-small-cell lung cancer

EZH2 inhibitors reverse resistance to gefitinib in primary EGFR wild-type lung cancer cells

Ezh2 Inhibitors Reverse Resistance to Gefitinib in Primary Egfr Wild-type Lung Cancer Cells

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