Blockade of Hedgehog Signaling Synergistically Increases Sensitivity to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer Cell Lines

Bai, Xiaoyan; Zhang, Xuchao; Yang, Shibin; An, Shejuan; Chen, Zhihong; Su, Jian; Xie, Zhi; Gou, Lan-ying; Wu, Yi‐Long

doi:10.1371/journal.pone.0149370

Cited by 57 publications

(64 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Infact, protein lysates from harvested resistant tumors showed higher vimentin levels and EGFR-inhibitors resistant cancer cells established in vitro showed high invasive and migrative abilities. Consistently with our previous findings, Hh signaling was confirmed as an important mediator of resistance to EGFR-TKIs inhibitors for first-generation EGFR-TKIs [6, 30–32]. Further, in the present study, we demonstrated that Hh activation is involved also in resistance to second and third generation EGFR-TKIs.…”

Section: Discussionsupporting

confidence: 93%

Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR

et al. 2017

View full text Add to dashboard Cite

PurposeThe aim of this work was to investigate the efficacy of sequential treatment with first-, second- and third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and the mechanisms of acquired resistance occurring during the sequential use of these inhibitors.Experimental designWe developed an in vivo model of acquired resistance to EGFR-inhibitors by treating nude mice xenografted with HCC827, a human non-small-cell lung cancer (NSCLC) cell line harboring EGFR activating mutation, with a sequence of first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) (erlotinib and gefitinib), of second-generation EGFR-TKI (afatinib) plus/minus the anti-EGFR monoclonal antibody cetuximab, and of third-generation EGFR-TKI (osimertinib).ResultsHCC827-derived xenografts and with acquired resistance to EGFR-inhibitors were sensitive to the sequential use of first-, second- and third-generation EGFR-TKIs. Continuous EGFR inhibition of first-generation resistant tumors by sequential treatment with afatinib plus/minus cetuximab, followed by osimertinib, represented an effective therapeutic strategy in this model. Whereas T790M resistance mutation was not detected, a major mechanism of acquired resistance was the activation of components of the Hedgehog (Hh) pathway. This phenomenon was accompanied by epithelial-to-mesenchymal transition. Cell lines established in vitro from gefitinib-, or afatinib- or osimertinib-resistant tumors showed metastatic properties and maintained EGFR-TKIs resistance in vitro, that was reverted by the combined blockade of Hh, with the selective SMO inhibitor sonidegib, and EGFR.ConclusionsEGFR-mutant NSCLC can benefit from continuous treatment with EGFR-inhibitors, indepenently from mechanisms of resistance. In a complex and heterogenous scenario, Hh showed an important role in mediating resistance to EGFR-inhibitors through the induction of mesenchymal properties.

show abstract

Section: Discussionsupporting

confidence: 93%

Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Deregulated Sonic Hedgehog (SHH) pathway facilitates the initiation, progression and metastasis of NSCLC, confers drug resistance against targeted therapy and renders a lung cancer therapeutic interference option to cancer patients with poor prognosis 36–38 . Substantial studies have proved close relationship between aberrantly activated Hedgehog cascaded and chemo-drug resistance in lung cancer while downregulation of SHH pathway resensitizes cancer cells to conventional chemotherapy 7, 18, 20, 39, 40 .…”

Section: Discussionmentioning

confidence: 99%

Disruption of SHH signaling cascade by SBE attenuates lung cancer progression and sensitizes DDP treatment

Chen

Yang

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Deregulated Sonic Hedgehog (SHH) pathway facilitates the initiation, progression, and metastasis of Non-small cell lung cancer (NSCLC), confers drug resistance and renders a therapeutic interference option to lung cancer patients with poor prognosis. In this study, we screened and evaluated the specificity of a Chinese herb Scutellariabarbata D. Don extraction (SBE) in repressing SHH signaling pathway to block NSCLC progression. Our study confirmed that aberrant activation of the SHH signal pathway conferred more proliferative and invasive phenotypes to human lung cancer cells. This study revealed that SBE specifically repressed SHH signaling pathway to interfere the SHH-mediated NSCLC progression and metastasis via arresting cell cycle progression. We also found that SBE significantly sensitized lung cancer cells to chemotherapeutic agent DDP via repressing SHH components in vitro and in vivo. Mechanistic investigations indicated that SBE transcriptionally and specifically downregulated SMO and consequently attenuated the activities of GLI1 and its downstream targets in SHH signaling pathway, which interacted with cell cycle checkpoint enzymes to arrest cell cycle progression and lead to cellular growth inhibition and migration blockade. Collectively, our results suggest SBE as a novel drug candidate for NSCLC which specifically and sensitively targets SHH signaling pathway.

show abstract

“…33 However, a previous study reported that restoring E-cadherin expression can increase sensitivity to EGFR-TKIs. 34 The miRNAs identified in our study serve as markers to predict the mechanisms of acquired drug resistance in NSCLC without biopsy. The enforced miR-149-5p expression significantly induced the resistance of acquired-resistant cells to gefitinib treatment.…”

Section: Discussionmentioning

confidence: 89%

Genome-wide profiling of micro-RNA expression in gefitinib-resistant human lung adenocarcinoma using microarray for the identification of miR-149-5p modulation

Qin

Yan

et al. 2017

Tumour Biol.

View full text Add to dashboard Cite

To understand the mechanism involved in gefitinib resistance, we established gefitinib-resistant human HCC827/GR-8-1 cell line from the parental HCC827 cell line. We compared the micro-RNA expression profiles of the HCC827 cells HCC827/GR-8-1 using Agilent micro-RNA microarrays. The micro-RNAs, such as the miR-149-5p, were up-or downregulated and associated with acquired gefitinib resistance. Quantitative real-time polymerase chain reaction was then performed to verify the expression patterns of different micro-RNAs. The result showed that miR-149-5p was upregulated in the HCC827/GR-8-1 cell line. To investigate the biological function of miR-149-5p in non-small cell lung cancer cells acquired gefitinib resistance, we examined cell proliferation using a cell counting kit-8 assay. Cell viability was evaluated after the miR-149-5p mimics, inhibitors, and negative control were separately transfected into the non-small cell lung cancer cells. The results showed that the non-small cell lung cancer cells transfected with miR-149-5p mimics exhibited reduced cell motility. The drug-sensitivity assay results revealed that the overexpression of miR-149-5p effectively evaluates the half maximal inhibitory concentration values of the cell in response to gefitinib, and the downregulation of miR-149-5p can attenuate the half maximal inhibitory concentration values of the cell lines in response to gefitinib. Furthermore, the levels of miR-149-5p in the HCC827 and HCC827/GR-8-1 cells were inversely correlated with caspase-3 expression. In conclusion, this study revealed that miR-149-5p is upregulated in the HCC827/ GR-8-1 cells and involved in the acquired gefitinib resistance.

show abstract

Blockade of Hedgehog Signaling Synergistically Increases Sensitivity to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer Cell Lines

Cited by 57 publications

References 51 publications

Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR

Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR

Disruption of SHH signaling cascade by SBE attenuates lung cancer progression and sensitizes DDP treatment

Genome-wide profiling of micro-RNA expression in gefitinib-resistant human lung adenocarcinoma using microarray for the identification of miR-149-5p modulation

Contact Info

Product

Resources

About