scholarly journals NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

2016 ◽  
Vol 113 (18) ◽  
pp. E2526-E2535 ◽  
Author(s):  
Ching-Feng Chiu ◽  
Yi-Wen Chang ◽  
Kuang-Tai Kuo ◽  
Yu-Shiuan Shen ◽  
Chien-Ying Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Egfr Mutation ◽  
Lung Cancer Cells ◽  
Cancer Stemness ◽  
Lung Cancer Patients ◽  
Gefitinib Resistance ◽  
Egfr Tki ◽  
Egfr Tkis

Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs, such as gefitinib or erlotinib) significantly prolongs survival time for patients with tumors harboring an activated mutation on EGFR; however, up to 40% of lung cancer patients exhibit acquired resistance to EGFR-TKIs with an unknown mechanism. FOXO3a, a transcription factor of the forkhead family, triggers apoptosis, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we observed that a high level of FOXO3a was correlated with EGFR mutation-independent EGFR-TKI sensitivity, the suppression of cancer stemness, and better progression-free survival in lung cancer patients. The suppression of FOXO3a obviously increased gefitinib resistance and enhanced the stem-like properties of lung cancer cells; consistent overexpression of FOXO3a in gefitinib-resistant lung cancer cells reduced these effects. Moreover, we identified that miR-155 targeted the 3′UTR of FOXO3a and was transcriptionally regulated by NF-κB, leading to repressed FOXO3a expression and increased gefitinib resistance, as well as enhanced cancer stemness of lung cancer in vitro and in vivo. Our findings indicate that FOXO3a is a significant factor in EGFR mutation-independent gefitinib resistance and the stemness of lung cancer, and suggest that targeting the NF-κB/miR-155/FOXO3a pathway has potential therapeutic value in lung cancer with the acquisition of resistance to EGFR-TKIs.

scholarly journals Long non-coding RNA AFAP1-AS1 accelerates lung cancer cells migration and invasion by interacting with SNIP1 to upregulate c-Myc

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yu Zhong ◽  
Liting Yang ◽  
Fang Xiong ◽  
Yi He ◽  
Yanyan Tang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cancer Metastasis ◽  
Lung Cancer Cells ◽  
Migration And Invasion ◽  
Lung Cancer Patients ◽  
Lung Cancer Metastasis ◽  
Non Coding Rna ◽  
Long Non Coding Rna

AbstractActin filament associated protein 1 antisense RNA 1 (named AFAP1-AS1) is a long non-coding RNA and overexpressed in many cancers. This study aimed to identify the role and mechanism of AFAP1-AS1 in lung cancer. The AFAP1-AS1 expression was firstly assessed in 187 paraffin-embedded lung cancer and 36 normal lung epithelial tissues by in situ hybridization. The migration and invasion abilities of AFAP1-AS1 were investigated in lung cancer cells. To uncover the molecular mechanism about AFAP1-AS1 function in lung cancer, we screened proteins that interact with AFAP1-AS1 by RNA pull down and the mass spectrometry analyses. AFAP1-AS1 was highly expressed in lung cancer clinical tissues and its expression was positively correlated with lung cancer patients’ poor prognosis. In vivo experiments confirmed that AFAP1-AS1 could promote lung cancer metastasis. AFAP1-AS1 promoted lung cancer cells migration and invasion through interacting with Smad nuclear interacting protein 1 (named SNIP1), which inhibited ubiquitination and degradation of c-Myc protein. Upregulation of c-Myc molecule in turn promoted the expression of ZEB1, ZEB2, and SNAIL gene, which ultimately enhanced epithelial to mesenchymal transition (EMT) and lung cancer metastasis. Understanding the molecular mechanism by which AFAP1-AS1 promotes lung cancer’s migration and invasion may provide novel therapeutic targets for lung cancer patients’ early diagnosis and therapy.

Comprehensive cancer genomics-based screening of new therapeutic targets and biomarkers for lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21031-e21031
Author(s):  
Yataro Daigo ◽  
Atsushi Takano ◽  
Yusuke Nakamura
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Therapeutic Target ◽  
Cancer Genomics ◽  
Cancer Biomarkers ◽  
Lung Cancer Cells ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Target Molecules

e21031 Background: Since the clinical outcome of advanced lung cancer patients is still poor after standard therapies, development of new anti-cancer drugs with minimum risk of adverse effects and cancer biomarkers for precision medicine is urgently required. Methods: We have been screening new therapeutic target molecules and molecular biomarkers for lung cancers as follows; i) To identify overexpressed genes in lung cancers by the gene expression profile analysis, ii) To verify the target genes for their scarce expression in normal tissues, iii) To validate the clinicopathologic importance of their protein expression by tissue microarray covering 263 lung cancers, and iv) To confirm their function for the growth and/or invasive ability of the lung cancer cells by siRNAs and gene transfection assays. Results: We identified dozens of candidate target molecules and selected a gene encoding protein with a GAP domain, LAPG1 (lung cancer-associated protein with Gap domain 1). Immunohistochemical analysis showed that LAPG1 expression was observed in 69.9% of lung cancers. Moreover positivity of LAPG1 expression was associated with poor prognosis of lung cancer patients. Knockdown of LAPG1 expression by siRNAs suppressed growth of lung cancer cells. Introduction of LAPG1 increased the invasive activity of mammalian cells, indicating that LAPG1 could be a prognostic biomarker and therapeutic target for lung cancers. Conclusions: Comprehensive cancer genomics-based screening could be useful for selection of new cancer biomarkers and molecular targets for developing small molecules, antibodies, nucleic acid drugs, and immunotherapies.

scholarly journals Genetic diagnostic features after failure of initial treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors among non-small-cell lung cancer patients harboring EGFR mutations

2020 ◽  
Author(s):  
Yuichiro Takeda ◽  
Go Naka ◽  
Yoh Yamaguchi ◽  
Masao Hashimoto ◽  
Manabu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
First Line ◽  
Lung Cancer Patients ◽  
Epidermal Growth ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Background: Osimertinib, a third - generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as a second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than the first-generation EGFR-TKIs used for first-line treatment, its efficacy with respect to long-term patient survival remains unclear even upon the administration of a complete sequence of EGFR-TKI therapy, and limited information is available regarding genetic diagnostic approaches after EGFR-TKI naïve treatment. This study investigated the characteristics of EGFR-mutated lung cancer patients harboring the T790M substitution resistance to EGFR-TKIs and the advantages of rebiopsy and liquid biopsy for these patients. Methods: The medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs, except for osimertinib, single plexus cobas version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy. Results: From April 2016 through May 2019, 113 patients were determined to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among which 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, had new lesions, and were administered gefitinib as first-line therapy, patients harboring an EGFR mutation were suspected of harboring the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with co-existing original mutations, brain metastases, tumor enlargement by ≥ 12 mm, or metastases at minor sites. Conclusion: Repeated biopsy can help maximize the detection rate of the T790M substitution. Furthermore, the advantages of repeated tissue or liquid biopsy should be considered among patients with positive T790M factors , and these biopsies can be repeated numerous times .

scholarly journals Genetic diagnostic features after failure of initial treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors among non-small-cell lung cancer patients harboring EGFR mutations

2020 ◽  
Author(s):  
Yuichiro Takeda ◽  
Go Naka ◽  
Yoh Yamaguchi ◽  
Masao Hashimoto ◽  
Manabu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Liquid Biopsies ◽  
Lung Cancer Patients ◽  
Epidermal Growth ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Background: Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than the first-generation EGFR-TKIs used for first-line treatment, its efficacy with respect to long-term patient survival remains unclear even upon the administration of a complete sequence of EGFR-TKI therapy. Moreover, limited information is available regarding genetic diagnostic approaches after the treatment of EGFR-TKI–naïve patients. This study investigated the clinical characteristics of EGFR -mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs, as well as the advantages of rebiopsy and liquid biopsy for these patients. Methods: The medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs, except for osimertinib, single-plexus cobas version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy. Results: From April 2016 through May 2019, 113 patients were found to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among whom 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue biopsies and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, had a new lesion, and were administered gefitinib as first-line therapy, they were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with coexisting original mutations, brain metastases, tumor enlargement by ≥ 12 mm, or metastases at minor sites. Conclusion: Among patients with positive factors associated with the T790M mutation, repeated tissue or liquid biopsies are useful to maximize the detection rate of the T790M substitution. Furthermore, these biopsies need to be repeated numerous times in order to reduce “detection overlook” among such patients.

scholarly journals Genetic diagnostic features after failure of initial treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors among non-small-cell lung cancer patients harboring EGFR mutations

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yuichiro Takeda ◽  
Go Naka ◽  
Yoh Yamaguchi ◽  
Masao Hashimoto ◽  
Manabu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Growth Factor Receptor ◽  
First Line ◽  
Liquid Biopsies ◽  
Lung Cancer Patients ◽  
Epidermal Growth ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Background Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than the first-generation EGFR-TKIs used for first-line treatment, its efficacy with respect to long-term patient survival remains unclear even upon the administration of a complete sequence of EGFR-TKI therapy. Moreover, limited information is available regarding genetic diagnostic approaches after the treatment of EGFR-TKI–naïve patients. This study investigated the clinical characteristics of EGFR-mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs, as well as the advantages of rebiopsy and liquid biopsy for these patients. Methods The medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs, except for osimertinib, single-plexus cobas version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy. Results From April 2016 through May 2019, 113 patients were found to harbor EGFR mutations. Sixty patients were treated with EGFR-TKIs, among whom 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue biopsies and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, had a new lesion, and were administered gefitinib as first-line therapy, they were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with coexisting original mutations, brain metastases, tumor enlargement by ≥12 mm, or metastases at minor sites. Conclusion Among patients with positive factors associated with the T790M mutation, repeated tissue or liquid biopsies are useful to maximize the detection rate of the T790M substitution. Furthermore, these biopsies need to be repeated numerous times in order to reduce “detection overlook” among such patients.

scholarly journals DDX3X mediates EGFR-TKI resistance through VEGFR signaling

2021 ◽  
Author(s):  
Aya Ohtsubo ◽  
Hiroshi Kagamu ◽  
Satoshi Watanabe ◽  
Kunihiro Shono ◽  
Takaaki Masuda ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Antitumor Effects ◽  
Mesenchymal Transition ◽  
Tki Resistance ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are remarkably effective against non-small-cell lung cancer (NSCLC) with EGFR-activating mutations, lung cancer cells acquire resistance to EGFR-TKIs without exception. Several mechanisms of EGFR-TKI resistance have been reported, but there are many aspects that remain to be clarified. We previously identified DDX3X as an immunogenic protein preferentially expressed in murine melanoma with a cancer stem cell (CSC)-like phenotype. DDX3X induced epithelial-mesenchymal transition and reduced the sensitivity to EGFR-TKIs in PC9 cells, human lung cancer cells harboring EGFR exon 19 deletion. We also reported that there was a small nonadherent subpopulation of parental PC9 cells that highly expressed DDX3X and had CSC properties. In this study, we found that VEGFR2 was upregulated in lung cancer cells that strongly expressed DDX3X and that these cells were addicted to VEGFR signaling. The blockade of both EGFR and VEGFR signaling reduced the phosphorylation of downstream signals in the cells with DDX3X that acquired EGFR-TKI resistance. The addition of VEGFR-TKIs or anti-VEGF antibodies to EGFR-TKIs significantly inhibited the progression of EGFR-mutated NSCLC in a xenograft mouse model. These data suggest that the blockade of VEGFR signaling enhances the antitumor effects of EGFR-TKIs by eradicating cancer stem cells, which mediate resistance to EGFR-TKIs.

scholarly journals Capilliposide C from Lysimachia capillipes Restores Radiosensitivity in Ionizing Radiation-Resistant Lung Cancer Cells Through Regulation of ERRFI1/EGFR/STAT3 Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Kan Wu ◽  
Xueqin Chen ◽  
Jianguo Feng ◽  
Shirong Zhang ◽  
Yasi Xu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Lung Cancer Cells ◽  
Rna Seq ◽  
Lung Cancer Cell ◽  
Lung Cancer Patients ◽  
Damage Repair

AimsRadiation therapy is used as the primary treatment for lung cancer. Unfortunately, radiation resistance remains to be the major clinic problem for lung cancer patients. Lysimachia capillipes capilliposide C (LC-C), an extract from LC Hemsl, has demonstrated multiple anti-cancer effects in several types of cancer. Here, we investigated the potential therapeutic impacts of LC-C on radiosensitivity in lung cancer cells and their underlying mechanisms.MethodsNon-small cell lung cancer cell lines were initially irradiated to generate ionizing radiation (IR)-resistant lung cancer cell lines. RNA-seq analysis was used to examine the whole-transcriptome alteration in IR-resistant lung cancer cells treated with or without LC-C, and the differentially expressed genes with most significance were verified by RT-qPCR. Colony formation assays were performed to determine the effect of LC-C and the target gene ErbB receptor feedback inhibitor 1 (ERRFI1) on radiosensitivity of IR-resistant lung cancer cells. In addition, effects of ERRFI1 on cell cycle distribution, DNA damage repair activity were assessed by flow cytometry and γ-H2AX immunofluorescence staining respectively. Western blotting was performed to identify the activation of related signaling pathways. Tumor xenograft experiments were conducted to observe the effect of LC-C and ERRFI1 on radiosensitivity of IR-resistant lung cancer cells in vivo.ResultsCompared with parental cells, IR-resistant lung cancer cells were more resistant to radiation. LC-C significantly enhanced the effect of radiation in IR-resistant lung cancer cells both in vitro and in vivo and validated ERRFI1 as a candidate downstream gene by RNA-seq. Forced expression of ERRFI1 alone could significantly increase the radiosensitivity of IR-resistant lung cancer cells, while silencing of ERRFI1 attenuated the radiosensitizing function of LC-C. Accordingly, LC-C and ERRFI1 effectively inhibited IR-induced DNA damage repair, and ERRFI1 significantly induced G2/M checkpoint arrest. Additional investigations revealed that down-regulation of EGFR/STAT3 pathway played an important role in radiosensitization between ERRFI1 and LC-C. Furthermore, the high expression level of ERRFI1 was associated with high overall survival rates in lung cancer patients.ConclusionsTreatment of LC-C may serve as a promising therapeutic strategy to overcome the radiation resistance and ERRFI1 may be a potential therapeutic target in NSCLC.

scholarly journals Genetic diagnostic features after failure of initial treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors among non-small-cell lung cancer patients harboring EGFR mutations

2020 ◽  
Author(s):  
Yuichiro Takeda ◽  
Go Naka ◽  
Yoh Yamaguchi ◽  
Masao Hashimoto ◽  
Manabu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
First Line ◽  
Lung Cancer Patients ◽  
Epidermal Growth ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Background: Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), can be used as second-line treatment for lung cancer patients harboring the T790M substitution. Although osimertinib is more effective than first-generation EGFR-TKIs used for first-line treatment, their efficacy for long-term patient survival remains unclear even upon administration of a complete sequence of EGFR-TKI therapy, and limited information is available regrading genetic diagnostic approaches after EGFR-TKI naïve treatment. This study aimed to investigate the characteristics of EGFR-mutated lung cancer patients harboring the T790M substitution resistant to EGFR-TKIs and the advantages of rebiopsy and liquid biopsy among these patients.Methods: The medical records of patients screened for EGFR mutations were reviewed. Upon failure of naïve treatment with EGFR-TKIs except for osimertinib, single plexus COBAS version 2 was repeatedly used to detect the T790M substitution in EGFR via tissue or liquid biopsy. Results: From April 2016 through May 2019, 113 patients harbored EGFR mutations. Sixty patients were treated with EGFR-TKIs, among which 46 underwent tissue or liquid biopsy. Twenty-nine of these 46 (63%) patients harbored the T790M substitution. In total, 141 rebiopsies were performed. The T790M substitution was detected in 24 of 43 tissue and 11 of 98 liquid biopsies. If patients displayed an EGFR exon 19 deletion, displayed a new lesion, and were administered gefitinib as first-line therapy, patients harboring an EGFR mutation were suspected to harbor the T790M substitution. Furthermore, the T790M substitution was detected through rebiopsy in patients with co-existing original mutations, brain metastases, tumor enlargement by ≥ 12 mm, or metastases at rare sites. Conclusion: Repeated biopsy can help maximize the detection rate of the T790M substitution. Furthermore, the advantages of repeated tissue or liquid biopsy should be considered among patients with positive T790M factors, and these biopsies can be repeated numerous times.

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