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Significance of SALL4 as a drug resistant factor in lung cancer

ABSTRACT: To examine the mechanism by which SALL4 regulates drug sensitivity, approximately 65,000 molecules on a microarray chip were analyzed using lung cancer cells transduced with a SALL4 vector (pCMV6-SALL4) or a control vector (pCMV6-Mock) . SALL4 mRNA and protein expression markedly increased after 24 hr of SALL4 vector transduction, unlike that in the cells transduced with the control vector; these cells were used for microarray analysis.

ORGANISM(S): Homo sapiens

SUBMITTER: Yanagihara Nozomi

PROVIDER: S-ECPF-GEOD-56595 | biostudies-other |

REPOSITORIES: biostudies-other

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Significance of SALL4 as a drug resistant factor in lung cancer

Project description:To examine the mechanism by which SALL4 regulates drug sensitivity, approximately 65,000 molecules on a microarray chip were analyzed using lung cancer cells transduced with a SALL4 vector (pCMV6-SALL4) or a control vector (pCMV6-Mock) . SALL4 mRNA and protein expression markedly increased after 24 hr of SALL4 vector transduction, unlike that in the cells transduced with the control vector; these cells were used for microarray analysis.

2014-04-30 | E-GEOD-56595 | biostudies-arrayexpress

Significance of SALL4 as a drug resistant factor in lung cancer

2014-04-30 | GSE56595 | GEO

Targeting SALL4 by entinostat in lung cancer.

Project description:The overall survival of lung cancer patients remains dismal despite the availability of targeted therapies. Oncofetal protein SALL4 is a novel cancer target. We herein report that SALL4 was aberrantly expressed in a subset of lung cancer patients with poor survival. SALL4 silencing by RNA interference or SALL4 peptide inhibitor treatment led to impaired lung cancer cell growth. Expression profiling of SALL4-knockdown cells demonstrated that both the EGFR and IGF1R signaling pathways were affected. Connectivity Map analysis revealed the HDAC inhibitor entinostat as a potential drug in treating SALL4-expressing cancers, and this was confirmed in 17 lung cancer cell lines. In summary, we report for the first time that entinostat can target SALL4-positive lung cancer. This lays the foundation for future clinical studies evaluating the therapeutic efficacy of entinostat in SALL4-positive lung cancer patients.

| S-EPMC5342750 | biostudies-literature

The Significance of MicroRNAs Expression in Regulation of Extracellular Matrix and Other Drug Resistant Genes in Drug Resistant Ovarian Cancer Cell Lines.

Project description:Ovarian cancer rates the highest mortality among all gynecological malignancies. The main reason for high mortality is the development of drug resistance. It can be related to increased expression of drug transporters and increased expression of extracellular matrix (ECM) proteins. Our foremost aim was to exhibit alterations in the miRNA expression levels in cisplatin (CIS), paclitaxel (PAC), doxorubicin (DOX), and topotecan (TOP)-resistant variants of the W1 sensitive ovarian cancer cell line-using miRNA microarray. The second goal was to identify miRNAs responsible for the regulation of drug-resistant genes. According to our observation, alterations in the expression of 40 miRNAs were present. We could observe that, in at least one drug-resistant cell line, the expression of 21 miRNAs was upregulated and that of 19 miRNAs was downregulated. We identified target genes for 22 miRNAs. Target analysis showed that miRNA regulates key genes responsible for drug resistance. Among others, we observed regulation of the ATP-binding cassette subfamily B member 1 gene (ABCB1) in the paclitaxel-resistant cell line by miR-363 and regulation of the collagen type III alpha 1 chain gene (COL3A1) in the topotekan-resistant cell line by miR-29a.

| S-EPMC7177408 | biostudies-literature

Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition

Project description:A subset of lung adenocarcinomas is driven by the EML4-ALK translocation. Even though ALK inhibitors in the clinic lead to excellent initial responses, acquired resistance to these inhibitors due to on-target mutations or parallel pathway alterations is a major clinical challenge. Exploring these mechanisms of resistance, we found that EML4-ALK cells parental or resistant to crizotinib, ceritinib or alectinib are remarkably sensitive to inhibition of CDK7/12 with THZ1 and CDK9 with alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti-apoptotic genes. Importantly, alvocidib reduced tumour progression in xenograft mouse models. In summary, our study takes advantage of the transcriptional addiction hypothesis to propose a new treatment strategy for a subset of patients with acquired resistance to first, second and third-generation ALK inhibitors.

| S-SCDT-EMM-2019-11099P | biostudies-other

miRNA sequence analysis of drug-resistant small cell lung cancer

Project description:We obtained small cell lung cancer specimens and normal lung specimens from patients who died of drug-resistant SCLC. The small lung cancer specimens include primary lesions and metastatic lesions. Next generation sequencing was performed to assess the expression of miRNA in drug-resistant small cell lung cancer.

2021-06-05 | GSE176198 | GEO

Targeting microtubules sensitizes drug resistant lung cancer cells to lysosomal pathway inhibitors.

Project description:Oncogene-addicted cancers are predominantly driven by specific oncogenic pathways and display initial exquisite sensitivity to designer therapies, but eventually become refractory to treatments. Clear understanding of lung tumorigenic mechanisms is essential for improved therapies. Methods: Lysosomes were analyzed in EGFR-WT and mutant cells and corresponding patient samples using immunofluorescence or immunohistochemistry and immunoblotting. Microtubule organization and dynamics were studied using immunofluorescence analyses. Also, we have validated our findings in a transgenic mouse model that contain EGFR-TKI resistant mutations. Results: We herein describe a novel mechanism that a mutated kinase disrupts the microtubule organization and results in a defective endosomal/lysosomal pathway. This prevents the efficient degradation of phosphorylated proteins that become trapped within the endosomes and continue to signal, therefore amplifying downstream proliferative and survival pathways. Phenotypically, a distinctive subcellular appearance of LAMP1 secondary to microtubule dysfunction in cells expressing EGFR kinase mutants is seen, and this may have potential diagnostic applications for the detection of such mutants. We demonstrate that lysosomal-inhibitors re-sensitize resistant cells to EGFR tyrosine-kinase inhibitors (TKIs). Identifying the endosome-lysosome pathway and microtubule dysfunction as a mechanism of resistance allows to pharmacologically intervene on this pathway. Conclusions: We find that the combination of microtubule stabilizing agent and lysosome inhibitor could reduce the tumor progression in EGFR TKI resistant mouse models of lung cancer.

| S-EPMC7052910 | biostudies-literature

Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition

Project description:A subset of lung adenocarcinomas is driven by the EML4-ALK translocation. Despite excellent initial responses in patients, acquired resistance to ALK inhibitors occurs. Exploring these mechanisms of resistance, we found that EML4-ALK cells resistant to ALK inhibitors are remarkably sensitive to THZ1, alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti-apoptotic genes. In conclusion, this study shows that THZ1, alvocidib or dinaciclib could be a therapeutic option for a subset of patients with acquired resistance to first, second and third-generation ALK inhibitors.

2019-12-15 | E-MTAB-8563 | biostudies-arrayexpress

Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition

2019-12-22 | E-MTAB-8590 | biostudies-arrayexpress

Upregulation of SALL4 by EGFR activation regulates the stemness of CD44-positive lung cancer.

Project description:The transcriptional factor SALL4, an important stem cell regulator, is expressed in hematopoietic stem cells and various malignancies, but its role in EGFR-mutated NSCLCs has not been studied yet. Here, we report that the expression of Sal-like protein 4 (SALL4), was significantly higher in EGFR mutated lung tumors than in non-tumor tissue. SALL4-high lung cancer patients had poorer prognosis after surgery than SALL4-low patients. The expression of SALL4 could be induced by the activation of EGFR through the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. The knockdown of SALL4 expression could suppress spheroid formation and the expression of lung cancer stem cell marker CD44. More interestingly, the knockdown of SALL4 expression could suppress the migration, invasion, and metastasis of the lung cancer cells and significantly increase the sensitivity of EGFR mutated cells to Erlotinib. These results suggest that SALL4 may be a novel potential therapeutic target for the diagnosis and treatment of lung cancer.

| S-EPMC5915399 | biostudies-literature

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