scholarly journals Cell Line Models for Acquired Resistance to First-Line Osimertinib in Lung Cancers—Applications and Limitations

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 354
Author(s):  
Shuta Ohara ◽  
Kenichi Suda ◽  
Tetsuya Mitsudomi
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Second Generation ◽  
Acquired Resistance ◽  
Research Groups ◽  
First Line ◽  
Lung Cancers ◽  
Mesenchymal Transition ◽  
First And Second Generation ◽  
Egfr Tkis

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are first-line drugs for lung cancers with activating EGFR mutations. Although first- and second-generation EGFR-TKIs were standard first-line treatments, acquired resistance (AR) to these drugs is almost inevitable. Cell line models have been widely used to explore the molecular mechanisms of AR to first- and second-generation EGFR-TKIs. Many research groups, including ours, have established AR cell lines that harbor the EGFR T790M secondary mutation, MET gene amplification, or epithelial–mesenchymal transition (EMT) features, which are all found in clinical specimens obtained from TKI-refractory lesions. Currently, many oncologists prescribe osimertinib, a third-generation EGFR-TKI that can overcome T790M-mediated resistance, as a first-line TKI. Although few clinical data are available about AR mechanisms that arise when osimertinib is used as a first-line therapy, many research groups have established cell lines with AR to osimertinib and have reported on their AR mechanisms. In this review, we summarize the findings on AR mechanisms against first-line osimertinib obtained from analyses of cell line models.

scholarly journals A Gain of Function Mutation in the NSD2 Histone Methyltransferase Drives Glucocorticoid Resistance Via Blocking Receptor Auto-Induction and BIM/Bmf Expression in ALL

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3758-3758
Author(s):  
Jianping Li ◽  
Catalina Troche ◽  
Julia Hlavka Zhang ◽  
Jonathan Shrimp ◽  
Jacob S. Roth ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Cell Lines ◽  
Mutant Allele ◽  
Gene Editing ◽  
Conflicts Of Interest ◽  
Chemotherapeutic Agents ◽  
Rna Seq ◽  
Mesenchymal Transition ◽  
Pediatric All

Despite improvements in chemotherapy that have increased the 5-year survival rates of pediatric ALL to close to 90%, 15-20% of patients may relapse with a very poor prognosis. Pediatric ALL patients, particularly those in relapse can harbor a specific point mutation (E1099K) in NSD2 (nuclear receptor binding SET domain protein 2) gene, also known as MMSET or WHSC1, which encodes a histone methyl transferase specific for H3K36me2. To understand the biology of mutant NSD2, we used CRISPR-Cas9 gene editing to disrupt the NSD2E1099K mutant allele in B-ALL cell lines (RCH-ACV and SEM) and T-ALL cell line (RPMI-8402) or insert the E1099K mutation into the NSD2WT T-ALL cell line (CEM) and B-ALL cell line (697). Cell lines in which the NSD2E1099K mutant allele is present display increased global levels of H3K36me2 and decreased H3K27me3. NSD2E1099Kcells demonstrate enhanced cell growth, colony formation and migration. NSD2E1099K mutant cell lines assayed by RNA-Seq exhibit an aberrant gene signature, mostly representing gene activation, with activation of signaling pathways, genes implicated in the epithelial mesenchymal transition and prominent expression of neural genes not generally found in hematopoietic tissues. Accordingly, NSD2E1099K cell lines showed prominent tropism to the central neural system in xenografts. To understand why this NSD2 mutations are identified prominently in children who relapse early from therapy for ALL, we performed high-throughput screening in our isogenic cell lines with the National Center for Advancing Translation Science (NCATS) Pharmaceutical Collection and other annotated chemical libraries and found that NSD2E1099K cells are resistant to glucocorticoids (GC) but not to other chemotherapeutic agents used to treat ALL such as vincristine, doxorubicin, cyclophosphamide, methotrexate, and 6-mercaptopurine. Accordingly, patient-derived-xenograft ALL cells with NSD2E1099K mutation were resistant to GC treatment. Reversion of NSD2E1099K mutation to NSD2WT restored GC sensitivity to both B- and T-ALL cell lines, which was accompanied by cell cycle arrest in G1 and induced-apoptosis. Furthermore, knock-in of the NSD2E1099K mutation conferred GC resistance to ALL cell lines by triggering cell cycle progression, proliferation and anti-apoptotic processes. Mice with NSD2E1099K xenografts were completely resistant to GC treatment while treatment of mice injected with isogenic NSD2WT cells led to significant tumor reduction and survival benefit. To illustrate these biological phenotypes and understand the molecular mechanism of GC resistance driven by NSD2E1099Kmutation, we investigated the GC-induced transcriptome, GC receptor (GR) binding sites and related epigenetic changes in isogenic ALL cell lines in response to GC treatment. RNA-Seq showed that GC transcriptional response was almost completely blocked in NSD2E1099K cells, especially in T-ALL cell lines, correlating with their lack of biological response. GC treatment activated apoptotic pathways and downregulated cell cycle and DNA repair pathways only in NSD2WT cells. The critical pro-apoptotic regulators BIM and BMF failed to be activated by GC in NSD2E1099K cells but were prominently activated when the NSD2 mutation was removed. Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that, the NSD2E1099K mutation blocked the ability of GR and CTCF to bind most GC response elements (GREs) such as those within BIM and BMF. While GR binding in NSD2WT cells was accompanied by increased H3K27 acetylation and gene expression, this failed to occur in NSD2 mutant cells. Furthermore, we found that GR RNA and protein levels were repressed in ALL cells expressing NSD2E1099K and GC failed to induce GR expression in these cells. Paradoxically, while H3K27me3 levels were generally decreased in NSD2E1099K cells, we saw increased levels of H3K27me3 at the GRE within the GR gene body where GR itself and CTCF normally bind, suggesting a novel role for the polycomb repressive complex 2 and EZH2 inhibitors for this form of GC resistance. In conclusion, these studies demonstrate that NSD2E1099K mutation may play an important role in treatment failure of pediatric ALL relapse by interfering with the GR expression and its ability to bind and activate key target genes. Gene editing screens are being performed to understand how to overcome this resistance. Disclosures No relevant conflicts of interest to declare.

scholarly journals Preclinical Efficacy and Involvement of AKT, mTOR, and ERK Kinases in the Mechanism of Sulforaphane against Endometrial Cancer

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1273 ◽  
Author(s):  
Rajani Rai ◽  
Kathleen Gong Essel ◽  
Doris Mangiaracina Benbrook ◽  
Justin Garland ◽  
Yan Daniel Zhao ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
M Cell ◽  
Vimentin Expression ◽  
Western Blots ◽  
Endometrial Cancer Cell ◽  
Mesenchymal Transition

Sulforaphane exerts anti-cancer activity against multiple cancer types. Our objective was to evaluate utility of sulforaphane for endometrial cancer therapy. Sulforaphane reduced viability of endometrial cancer cell lines in association with the G2/M cell cycle arrest and cell division cycle protein 2 (Cdc2) phosphorylation, and intrinsic apoptosis. Inhibition of anchorage-independent growth, invasion, and migration of the cell lines was associated with sulforaphane-induced alterations in epithelial-to-mesenchymal transition (EMT) markers of increased E-cadherin and decreased N-cadherin and vimentin expression. Proteomic analysis identified alterations in AKT, mTOR, and ERK kinases in the networks of sulforaphane effects in the Ishikawa endometrial cancer cell line. Western blots confirmed sulforaphane inhibition of AKT, mTOR, and induction of ERK with alterations in downstream signaling. AKT and mTOR inhibitors reduced endometrial cancer cell line viability and prevented further reduction by sulforaphane. Accumulation of nuclear phosphorylated ERK was associated with reduced sensitivity to the ERK inhibitor and its interference with sulforaphane activity. Sulforaphane induced apoptosis-associated growth inhibition of Ishikawa xenograft tumors to a greater extent than paclitaxel, with no evidence of toxicity. These results verify sulforaphane’s potential as a non-toxic treatment candidate for endometrial cancer and identify AKT, mTOR, and ERK kinases in the mechanism of action with interference in the mechanism by nuclear phosphorylated ERK.

scholarly journals Establishment and characterization of a chordoma cell line from the tissue of a patient with dedifferentiated-type chordoma

2016 ◽  
Vol 25 (5) ◽  
pp. 626-635 ◽  
Author(s):  
Jeong-Yub Kim ◽  
Jongsun Lee ◽  
Jae-Soo Koh ◽  
Myung-Jin Park ◽  
Ung-Kyu Chang
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Cell Lines ◽  
Nude Mice ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Wide Resection ◽  
Cell Cycle Distribution ◽  
Facs Analysis ◽  
Mesenchymal Transition

OBJECTIVE Chordoma is a rare bone tumor of the axial skeleton believed to originate from the remnants of the embryonic notochord. The available tumor cells are characteristically physaliferous and express brachyury, a transcription factor critical for mesoderm specification. Although chordomas are histologically not malignant, treatments remain challenging because they are resistant to radiation therapy and because wide resection is impossible in most cases. Therefore, a better understanding of the biology of chordomas using established cell lines may lead to the advancement of effective treatment strategies. The authors undertook a study to obtain this insight. METHODS Chordoma cells were isolated from the tissue of a patient with dedifferentiated-type chordoma (DTC) that had recurred. Cells were cultured with DMEM/F12 containing 10% fetal bovine serum and antibiotics (penicillin and streptomycin). Cell proliferation rate was measured by MTS assay. Cell-cycle distribution and cell surface expression of proteins were analyzed by fluorescence-activated cell sorting (FACS) analysis. Expression of proteins was analyzed by Western blot and immunocytochemistry. Radiation resistance was measured by clonogenic survival assay. Tumor formation was examined by injection of chordoma cells at hindlimb of nude mice. RESULTS The putative (DTC) cells were polygonal and did not have the conventional physaliferous characteristic seen in the U-CH1 cell line. The DTC cells exhibited similar growth rate and cell-cycle distribution, but they exhibited higher clonogenic activity in soft agar than U-CH1 cells. The DTC cells expressed high levels of platelet-derived growth factor receptor–β and a low level of brachyury and cytokeratins; they showed higher expression of stemness-related and epithelial to mesenchymal transition–related proteins than the U-CH1 cells. Intriguingly, FACS analysis revealed that DTC cells exhibited marginal surface expression of CD24 and CD44 and high surface expression of CXCR4 in comparison to U-CH1 cells. In addition, blockade of CXCR4 with its antagonist AMD3100 effectively suppressed the growth of both cell lines. The DTC cells were more resistant to paclitaxel, cisplatin, etoposide, and ionizing radiation than the U-CH1 cells. Injection of DTC cells into the hindlimb region of nude mice resulted in the efficient formation of tumors, and the histology of xenograft tumors was very similar to that of the original patient tumor. CONCLUSIONS The use of the established DTC cells along with preestablished cell lines of chordoma may help bring about greater understanding of the mechanisms underlying the chordoma that will lead to therapeutic strategies targeting chordomas.

scholarly journals Identifying Mechanisms Associated with Venetoclax Resistance in Multiple Myeloma (MM)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2668-2668
Author(s):  
Yuan Xiao Zhu ◽  
Laura Ann Bruins ◽  
Joseph Ahmann ◽  
Cecilia Bonolo De Campos ◽  
Esteban Braggio ◽  
...  
Keyword(s):  
Cell Line ◽  
Board Of Directors ◽  
Cell Lines ◽  
Acquired Resistance ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Sensitive Cell ◽  
Advisory Committees ◽  
Bcl2 Family ◽  
Family Regulation

Abstract Venetoclax (VTX) is a selective small-molecule inhibitor of BCL-2 that exhibits antitumoral activity against MM cells presenting lymphoid features and those with translocation t(11;14). Despite its impressive clinical activity, VTX therapy for a prolonged duration can lead to drug resistance. Therefore, it is important to understand the underlying mechanisms of resistance in order to develop strategies to prevent or overcome resistance. In the present study, we established four VTX resistant human myeloma cell lines (HMCLs) from four sensitive HMCLs, including three with t(11;14), in culture with a stepwise increase in treatment dose with VTX. To identify the molecular basis of acquired VTX resistance, whole exon sequencing (WES), mRNA-sequencing (mRNAseq), and protein expression assays were performed in the four isogenic VTX-sensitive/resistant HMCLs and three MM patients with samples collected before VTX administration and after clinical resistance to the drug. Compared with sensitive cell lines and patient samples collected before VTX administration, mRNAseq analysis identified downregulation of BIM and upregulation of BCLXL in both resistant cell lines and MM cells from relapse patients. Other transcriptional changes detected included upregulation of AURKA, BIRC3, BIRC5, and IL32. Enrichment analysis of differentially expressed genes suggested involvement of PI3K and MAPK signaling, likely associated with cytokines, growth factors (EGF, FGF and IGF family members), and receptor tyrosine kinase (EGF and FGF). Western blot analysis was performed to compare BCL2 family expression in resistant cell lines versus sensitive cell lines and it showed upregulation of BCL2 survival members (such as MCL-1 and BCLXL), and downregulation of pro-apoptotic BH3 members (such as BIM and PUMA). BIM expression was completely lost in one resistant cell line, and introduction of exogenous BIM into this cell line enhanced VTX sensitivity. Interestingly, BCL2 was upregulated in some resistant cell lines generated after a long-term treatment with VTX, suggesting BCL2 expression level may not be suitable as a marker of VTX sensitivity for acquired resistance. Unlike in CLL, BCL2 mutations were not identified through WES in any resistant cell lines or primary patient sample harvested after relapse. While 8 genes were mutated in two resistant samples , no clear mutational pattern emerged . Based on the above, we further tested some specific inhibitors in in vitro or ex vivo cell models to help understanding resistant mechanism and identify strategies to overcome VTX resistance. We found that inhibition of MCL-1, with the compound S68345, substantially enhanced VTX sensitivity in three resistant HMCLs and in primary cells from one relapsed MM patient. A BCLXL inhibitor (A155463) only significantly enhanced VTX sensitivity in one resistant cell line after co-treatment with VTX. Co-treatment of the other three resistant cell lines with VTX, S68345 and A155463 resulted in the most synergistic anti-myeloma activity, suggesting those cell lines are co-dependent on MCL-1, BCLXL, and BCL2 for survival, although they are more dependent on MCL-1. We also found that inhibition of PI3K signaling, IGF1, RTK (EGF and FGF) and AURKA significantly increased VTX sensitivity, partially through downregulation of MCL-1, and BCLXL, and upregulation of BIM. Conventional anti-MM drugs such as dexamethasone, bortezomib and lenalidomide, were shown to have little activity on augmenting VTX sensitivity in most resistant cell lines. In summary, we find that acquired resistance to VTX in MM is largely associated with BCL2 family regulation, including upregulation of survival members such as MCL-1, BCLXL, BCL2, and downregulation of pro-apoptotic members, especially BIM. Our study also indicates that upstream signaling involved in BCL2 family regulation during acquired resistance is likely related to cytokine, growth factor, and/or RTK-induced cell signaling such as PI3K. Co-inhibition of MCL-1, or BCLXL, as well as the upstream PI3K, RTK (FGF and EGF), IGF-1 mediated signaling were effective in overcoming VTX resistance. Disclosures Fonseca: Mayo Clinic in Arizona: Current Employment; Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Merck: Consultancy; Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; AbbVie: Consultancy; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees.

scholarly journals YES1amplification: a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics

2018 ◽  
Author(s):  
Pang-Dian Fan ◽  
Giuseppe Narzisi ◽  
Anitha D. Jayaprakash ◽  
Elisa Venturini ◽  
Nicolas Robine ◽  
...  
Keyword(s):  
Cell Line ◽  
Mutant Cell ◽  
Acquired Resistance ◽  
Transposon Mutagenesis ◽  
Egfr Inhibitors ◽  
Genomic Sequencing ◽  
Mechanisms Of Resistance ◽  
Lung Cancers ◽  
Lung Adenocarcinomas ◽  
Clinical Genomic

ABSTRACTIn approximately 30% of patients withEGFR-mutant lung adenocarcinomas whose disease progresses on EGFR inhibitors, the basis for acquired resistance remains unclear. We have integrated transposon mutagenesis screening in anEGFR-mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify novel mechanisms of resistance to EGFR inhibitors. The most prominent candidate genes identified by insertions in or near the genes during the screen wereMET, a gene whose amplification is known to mediate resistance to EGFR inhibitors, and the gene encoding the Src family kinase YES1. Cell clones with transposon insertions that activated expression ofYES1exhibited resistance to all three generations of EGFR inhibitors and sensitivity to pharmacologic and siRNA-mediated inhibition ofYES1. Analysis of clinical genomic sequencing data from cases of acquired resistance to EGFR inhibitors revealed amplification ofYES1in 5 cases, 4 of which lacked any other known mechanisms of resistance. Pre-inhibitor samples, available for 2 of the 5 patients, lackedYES1amplification. None of 136 post-inhibitor samples had detectable amplification of other Src family kinases (SRC, FYN).YES1amplification was also found in 2 of 17 samples fromALKfusion-positive lung cancer patients who had progressed on ALK TKIs. Taken together, our findings identify acquired amplification ofYES1as a novel, recurrent, and targetable mechanism of resistance to EGFR inhibition inEGFR-mutant lung cancers, and demonstrate the utility of transposon mutagenesis in discovering clinically relevant mechanisms of drug resistance.SIGNIFICANCEDespite high response rates to treatment with small molecule inhibitors of EGFR tyrosine kinase activity, patients withEGFR-mutant lung adenocarcinomas eventually develop resistance to these drugs. In many cases, the basis of acquired resistance remains unclear. We have used a transposon mutagenesis screen in anEGFR-mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify amplification ofYES1as a novel and targetable mechanism of resistance to EGFR inhibitors inEGFR-mutant lung cancers.

scholarly journals Anti-human lung cancer activities and survey of gluthation reductase and gluthation S transferase inhibition properties with molecular modeling studies of 2′-Hydroxy-5′-methyl-3′-nitroacetophenone: A pre-clinical trial study

2021 ◽  
Author(s):  
Yawei Dou ◽  
shanshan Lv ◽  
Attalla F. El-kott ◽  
Ayman E. El-kenawy
Keyword(s):  
Lung Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Human Lung ◽  
Antioxidant Properties ◽  
Human Lung Cancer ◽  
Lung Cancers ◽  
Anticancer Properties ◽  
Ic50 Values ◽  
Human Lung Carcinoma

IntroductionRecently, scientists have tried to increase organic chemistry productions for the treatment of many cancers such as lung cancers. In this regard, antioxidant molecules have a special place in the treatment of several cancers. The molecular docking method was found to calculate the biological activity of the 2′-Hydroxy-5′-methyl-3′-nitroacetophenone (2′-H-5′-M-3′-N) molecule against the enzymes studied.Material and methodsIn these calculations, the enzymes used are gluthation reductase (GR) enzyme and Glutathione S-Transferase (GT) enzyme, respectively. After the modeling calculations were completed, the ADME/T parameters were examined to calculate the future drug use properties of the 2′-H-5′-M-3′-N molecule. To survey the antioxidant properties of 2′-H-5′-M-3′-N, the DPPH test was used. Several human lung adenocarcinoma cell lines i.e., lung moderately differentiated adenocarcinoma (LC-2/ad), lung poorly differentiated adenocarcinoma (PC-14), and lung well-differentiated bronchogenic adenocarcinoma (HLC-1) cell lines were used to determine the anticancer properties of the recent molecule.ResultsCell viability of 2′-H-5′-M-3′-N was very low against PC-14, LC-2/ad, and HLC-1 cell lines without any cytotoxicity on the normal cell line. The IC50 values of 2′-H-5′-M-3′-N against LC-2/ad, PC-14, and HLC-1 cell lines were found 475, 250, and 691 µg/mL, respectively. The best anti-human lung cancer properties of 2′-H-5′-M-3′-N against the above cell lines was in the case of PC-14 cell line.ConclusionsAs mentioned, the 2′-H-5′-M-3′-N had significant antioxidant and anti-human lung cancer properties. It appears that the anti-human lung carcinoma effect of 2′-H-5′-M-3′-N is due to their antioxidant effects.

scholarly journals Multi-Omics Characterization of the Spontaneous Mesenchymal–Epithelial Transition in the PMC42 Breast Cancer Cell Lines

2019 ◽  
Vol 8 (8) ◽  
pp. 1253 ◽  
Author(s):  
Sugandha Bhatia ◽  
James Monkman ◽  
Tony Blick ◽  
Pascal HG Duijf ◽  
Shivashankar H. Nagaraj ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phenotypic Plasticity ◽  
Cell Line ◽  
Cell Lines ◽  
Daughter Cell ◽  
Cancer Metastasis ◽  
Expression Profiles ◽  
Breast Cancer Cell Lines ◽  
Mesenchymal Transition ◽  
Mesenchymal Epithelial Transition

Epithelial–mesenchymal plasticity (EMP), encompassing epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET), are considered critical events for cancer metastasis. We investigated chromosomal heterogeneity and chromosomal instability (CIN) profiles of two sister PMC42 breast cancer (BC) cell lines to assess the relationship between their karyotypes and EMP phenotypic plasticity. Karyotyping by GTG banding and exome sequencing were aligned with SWATH quantitative proteomics and existing RNA-sequencing data from the two PMC42 cell lines; the mesenchymal, parental PMC42-ET cell line and the spontaneously epithelially shifted PMC42-LA daughter cell line. These morphologically distinct PMC42 cell lines were also compared with five other BC cell lines (MDA-MB-231, SUM-159, T47D, MCF-7 and MDA-MB-468) for their expression of EMP and cell surface markers, and stemness and metabolic profiles. The findings suggest that the epithelially shifted cell line has a significantly altered ploidy of chromosomes 3 and 13, which is reflected in their transcriptomic and proteomic expression profiles. Loss of the TGFβR2 gene from chromosome 3 in the epithelial daughter cell line inhibits its EMT induction by TGF-β stimulus. Thus, integrative ‘omics’ characterization established that the PMC42 system is a relevant MET model and provides insights into the regulation of phenotypic plasticity in breast cancer.

scholarly journals ACT-01 THE SECOND GENERATION ANAPLASTIC LYMPHOMA KINASE (ALK) INHIBITOR CERITINIB EFFECTIVELY INDUCES CELL DEATH IN HUMAN GLIOBLASTOMA CELLS

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii13-ii13
Author(s):  
Daisuke Kawauchi ◽  
Masamichi Takahashi ◽  
Shun Yamamuro ◽  
Tatsuya Kobayashi ◽  
Eita Uchida ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Anaplastic Lymphoma Kinase ◽  
Second Generation ◽  
Human Glioblastoma ◽  
Lung Cancers ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Alk Inhibitor ◽  
Type Gene

Abstract Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase which expresses only in the developmental stage of the brain during embryogenesis of human. On the other hand, a variety of ALK gene alterations, such as oncogenic fusion, activating point mutation, or wild type gene amplification, have been recently discovered as the powerful oncogene in various tumors, and these ALK mutations have also been known as the potential therapeutic targets against tumors harboring these ALK mutations. For example, ALK inhibitors have been already approved and used for the clinical treatment of non-small cell lung cancers harboring oncogenic ALK fusion. Previously, we reported classical ALK inhibitors triggered cell death in human glioblastoma (GBM) cells, which did not express ALK, via suppression of transcription factor STAT3 activation but not in normal tissue-derived cells. In this study, we investigated the anti-tumor effect of newly-developed ALK inhibitors in GBM cells. As a result, a second generation ALK inhibitor ceritinib induced cell death in various human GBM cell lines with lower concentration compared to other ALK inhibitors. Besides, ceritinib also suppressed STAT family activity in these GBM cell lines. From these results, we consider ceritinib might be a novel therapeutic agent against GBMs, and further investigation about the specific anti-tumor mechanism of ceritinib in GBM cells is currently on-going.

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