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  • American Association for Cancer Research (AACR)  (30)
  • 1
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    Online Resource
    Cdk5 Directly Targets Nuclear p21CIP1 and Promotes Cancer Cell Growth
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 23 ( 2016-12-01), p. 6888-6900
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 23 ( 2016-12-01), p. 6888-6900
    Abstract: The significance of Cdk5 in cell-cycle control and cancer biology has gained increased attention. Here we report the inverse correlation between the protein levels of Cdk5 and p21CIP1 from cell-based and clinical analysis. Mechanistically, we identify that Cdk5 overexpression triggers the proteasome-dependent degradation of p21CIP1 through a S130 phosphorylation in a Cdk2-independent manner. Besides, the evidence from cell-based and clinical analysis shows that Cdk5 primarily regulates nuclear p21CIP1 protein degradation. S130A-p21CIP1 mutant enables to block either its protein degradation or the increase of cancer cell growth caused by Cdk5. Notably, Cdk5-triggered p21CIP1 targeting primarily appears in S-phase, while Cdk5 overexpression increases the activation of Cdk2 and its interaction with DNA polymerase δ. The in vivo results show that Cdk2 might play an important role in the downstream signaling to Cdk5. In summary, these findings suggest that Cdk5 in a high expression status promotes cancer growth by directly and rapidly releasing p21CIP1-dependent cell-cycle inhibition and subsequent Cdk2 activation, which illustrates an oncogenic role of Cdk5 potentially applied for future diagnosis and therapy. Cancer Res; 76(23); 6888–900. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-15-3253
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 2
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    Abstract 417: Inflammation initiates OCT4/NANOG expression through IL-6-IGF-1R signaling activation and is associated with early recurrence of HBV-related HCC
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 417-417
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 417-417
    Abstract: Inflammatory microenvironment is a well-known promoter of hepatocellular carcinoma (HCC), a cancer with high rates of postoperative recurrence and poor prognosis. However, mechanisms underlying the inflammation-induced HCC promotion remain largely unknown. Here we demonstrate the effect of proinflammatory cytokine IL6 on IGF-1R signaling activation which initiates OCT4/NANOG expression and is associated with HBV-related HCC (HBV-HCC) recurrence. In this study, real-time quantitative PCR analysis demonstrated a high correlation between IGF-1R and OCT4/NANOG transcriptional expression in human HCC frozen tissues (N=119, R=0.8097 for OCT4; R= 0.8375 for NANOG). Interestingly, the OCT4, NANOG, or IGF-1R level in HBV-HCC was significantly higher than that in non HBV-HCC. Cultivation of cells in inflammation condition medium (Inflam-CM) increased OCT4/NANOG level in HBV+HBsAg+ cells (HepG2.2.15 and Hep3B), but not in HBV+HBsAg− (HA22T) or HBV−HBsAg− cells (HepG2 and Huh7). Epifluorescence/luciferase assay further demonstrated that Inflam-CM increased the GFP+ cell population as well as the luciferase activity of OCT4 promoter-GFP/luciferase-HepG2.2.15 cells. Besides, Inflam-CM significantly increased the IGF-1/IGF-1R transcriptional level and activated the IGF-1R signaling (phospho-IGF-1R and phospho-Akt) in HepG2.2.15 and Hep3B. Blockage of IGF-1R phosphorylation by picropodophyllin (PPP) dramatically decreased the OCT4/NANOG transcriptional activity. IL-6 stimulated the autocrinal IGF-I and IL-6 expression whereas AG490 (a phospho-STAT inhibitor) decreased the IGF-1R phosphorylation. The significant clinical association between early and overall postoperative recurrence and IGF-1R/OCT4/NANOG expression in both gene (real time RT-PCR) and protein (immunohistochemical staining) levels were demonstrated. When etiologic differences were considered, HBV-positive patients have the trend towards early HCC recurrence. Conclusion: Niche inflammatory stress might activate an autocrinal IL-6-IGF-I/IGF-1R-Akt signaling and OCT4/NANOG expression which is associated with early HBV-HCC recurrence. These results provide potential targets for individualized adjuvant therapy for HBV-HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 417. doi:1538-7445.AM2012-417
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-417
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 3
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    Regulation of Excision Repair Cross-Complementation Group 1 by Snail Contributes to Cisplatin Resistance in Head and Neck Cancer
    American Association for Cancer Research (AACR) ; 2010
    In:  Clinical Cancer Research Vol. 16, No. 18 ( 2010-09-15), p. 4561-4571
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 18 ( 2010-09-15), p. 4561-4571
    Abstract: Purpose: We investigated the mechanism and clinical significance of the epithelial-mesenchymal transition (EMT)-induced chemoresistance in head and neck squamous cell carcinoma (HNSCC). Experimental Design: The correlation between the expression of different EMT regulators and chemoresistance genes, such as excision repair cross complementation group 1 (ERCC1), was evaluated in cancer cell lines from the NCI-60 database and four human HNSCC cell lines. Ectopic expression of Snail or short-interference RNA-mediated repression of Snail or ERCC1 was done in HNSCC cell lines. Cell viability was examined for cells after cisplatin treatment. A luciferase reporter assay and chromatin immunoprecipitation were used to identify the transcriptional regulation of ERCC1 by Snail. Immunohistochemical analysis of Snail, Twist1, ERCC1, hypoxia inducible factor-1 α (HIF-1α), and NBS1 were done in samples from 72 HNSCC patients receiving cisplatin-based chemotherapy. Results: The correlation between the expression of Snail and ERCC1 was confirmed in different cell lines, including HNSCC cells. In HNSCC cell lines, overexpression of Snail in the low endogenous Snail/ERCC1 cell lines FaDu or CAL-27 increased ERCC1 expression, and hypoxia or overexpression of NBS1 also upregulated ERCC1. Knockdown of Snail in the high endogenous Snail/ERCC1 cell line OECM-1 downregulated ERCC1 expression and attenuated cisplatin resistance. Furthermore, suppression of ERCC1 in Snail- or NBS1-overexpressing HNSCC cells enhanced sensitivity to cisplatin. Snail directly regulated ERCC1 transcription. In patients with HNSCC, coexpression of Snail and ERCC1 correlated with cisplatin resistance and a poor prognosis. Conclusions: Activation of ERCC1 by Snail is critical in the generation of cisplatin resistance of HNSCC cells. Clin Cancer Res; 16(18); 4561–71. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-10-0593
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 4
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    Abstract 955: Preclinical characterization of a novel SSEA-4-targeting antibody drug conjugate, OBI-998
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 955-955
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 955-955
    Abstract: Stage-specific embryonic antigen-4 (SSEA-4) ceramide, a globo-series hexasaccharide glycosphingolipid, has been reported to be a tumor-associated antigen. Here, we present a novel antibody-drug conjugate (ADC) targeting SSEA-4 to evaluate its potential as a therapeutic agent for cancer treatment. OBI-998 is an ADC comprising the humanized anti-SSEA-4 antibody (OBI-898) that is conjugated to the highly potent microtubule-disrupting agent monomethyl auristatin E (MMAE) through maleimide and PEGylated cleavable linkers. We demonstrated the specificity of the naked antibody to SSEA-4 by screening against a panel of 21 related carbohydrate antigens using ELISA. OBI-998 displayed potent cytotoxic activity against cells (SKOV3) with a high level of SSEA-4 expression at sub-nanomolar potency but no effect on the viability of cells (SKBR3) with negligible SSEA-4 expression. The bystander killing effect of OBI-998 was shown by the transferring of conditioned medium from SKOV3 cells treated with 1 or 5 nM of OBI-998 to SKBR3 cells. Furthermore, significant bystander effects were observed by co-culturing high (NCI-N87) and low (PANC-1/GFP) SSEA-4-expressing cell lines at different ratios in the presence of 5 or 10 nM of OBI-998. OBI-998 was found to be rapidly internalized into cancer cells within 5 minutes upon binding to its target on the cell surface by confocal microscopy. OBI-998 showed significant anti-tumor efficacy in multiple cancer cell–derived xenograft models at doses of 1, 3, and 10 mg/kg in a dose-dependent manner. More importantly, OBI-998 at a dose of 10 mg/kg showed complete tumor regression in an EGFR-triple mutation non–small cell lung cancer xenograft model, which is resistant to the current last-line tyrosine kinase inhibitor, osimertinib. Pharmacokinetic analysis of OBI-998 revealed that total antibody and the conjugated antibody exhibited similar pharmacokinetic profiles, suggesting OBI-998 is highly stable in vivo. The biodistribution study in HCC1428 tumor-bearing mice indicated that MMAE accumulated in the tumor site at a higher level compared with other blood-rich organs. In addition, the MMAE levels in tumors reached peak level at 24 hours post-treatment, which was much higher than the maximum levels in other organs, and the level was sustained for 168 hours with tumor-to-muscle ratio of 329. OBI-998 is a novel ADC targeting SSEA-4 that possesses desired properties such as high target specificity, rapid internalization, potent cytotoxicity, and significant bystander effects. Furthermore, OBI-998 showed a high level of deposition and a persistent presence of MMAE in tumors and significant anti-tumor efficacy in a variety of animal models. Taken together, these results support the further development of OBI-998 as a therapeutic agent for SSEA-4-targeting cancer therapy. Citation Format: I-Ju Chen, Chun-Chung Wang, Chi-Sheng Shia, Chung-Chen Su, Chi-Huan Lu, Hui-Wen Chang, Ping-Tzu Chiu, Yueh-Chin Wu, Ming-Tain Lai, Wei-Chien Tang, Hsin-Yi Tung, Ren-Yu Hsu. Preclinical characterization of a novel SSEA-4-targeting antibody drug conjugate, OBI-998 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 955.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-955
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 5
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    Abstract 105: An epigenetic vicious cycle of DNMT, protein Tyrosine phosphatase receptor type R, and the MAPK pathway in cancer metastasis
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 105-105
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 105-105
    Abstract: Introduction: Epigenetic modifications are a driving force in carcinogenesis. In addition to its role in initiation and promotion, DNA methylation is thought to participate in cancer metastasis. The present study is to interrogate the role of de novo DNA methylation in cervical cancer invasions. Methods and Results: Here, we report evidence of the overexpression of DNA methyltransferases 3B (DNMT3B) in invasive cervical cancer and that DNMT3B interference inhibits metastasis. Using methyl-DNA immunoprecipitation coupled with microarray analysis (mDIP-on-chip), we found that Protein Tyrosine Phosphatase Receptor Type R (PTPRR) is targeted by DNMT3B. PTPRR inhibited metastasis by inhibiting p44/42 MAPK signaling, epithelial-mesenchymal transition (EMT), and matrix metalloproteinase 9 (MMP9) expression. PTPRR also inhibited the expression of transcription factor AP1, HPV oncogenes, and DNMTs, and reciprocally demethylated the PTPRR promoter. The methylation status of PTPRR was increased in cervical scrapings in accordance with disease severities, and immunohistochemical staining confirmed that PTPRR protein was expressed in precancerous lesions but was silenced in invasive cancers. The clinical correlation results suggest that methylation of the PTPRR promoter is a potential biomarker for cervical cancer detection. Conclusion: This study demonstrates for the first time that DNMT3B plays an important role in the cervical cancer invasion and metastasis. The DNMT3B-mediated silencing of PTPRR activates p44/42 MAPK signaling and its multiple downstream effectors such as EMT, enabling the in situ tumors becoming invasive. MAPK signaling also augments the expression of DNMTs, which further consolidates the methylation silencing of PTPRR. A vicious cycle between epigenetic machinery and oncogenic signaling promotes cancer metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 105. doi:10.1158/1538-7445.AM2011-105
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-105
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 6
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    Phosphoproteomics Reveals the Role of Constitutive KAP1 Phosphorylation by B-cell Receptor Signaling in Chronic Lymphocytic Leukemia
    American Association for Cancer Research (AACR) ; 2022
    In:  Molecular Cancer Research Vol. 20, No. 8 ( 2022-08-05), p. 1222-1232
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 8 ( 2022-08-05), p. 1222-1232
    Abstract: Application of B-cell receptor (BCR) pathway inhibitor ibrutinib for chronic lymphocytic leukemia (CLL) is a major breakthrough, yet the downstream effects following inhibition of BCR signaling and during relapse await further clarification. By comparative phosphoproteomic profiling of B cells from patients with CLL and healthy donors, as well as CLL B cells collected at multiple time points during the course of ibrutinib treatment, we provided the landscape of dysregulated phosphoproteome in CLL and its dynamic alterations associated with ibrutinib treatment. Particularly, differential phosphorylation events associated with several signaling pathways, including BCR pathway, were enriched in patient CLL cells. A constitutively elevated phosphorylation level of KAP1 at serine 473 (S473) was found in the majority of CLL samples prior to treatment. Further verification showed that BCR activation promoted KAP1 S473 phosphorylation, whereas ibrutinib treatment abolished it. Depletion of KAP1 in primary CLL cells decelerated cell-cycle progression and ectopic expression of a KAP1 S473 phospho-mimicking mutant accelerated G2–M cell-cycle transition of CLL cells. Moreover, temporal phosphoproteomic profiles using a series of CLL cells isolated from one patient during the ibrutinib treatment revealed the dynamic changes of several molecules associated with BCR signaling in the ibrutinib responsive and recurrent stages. Implications: This phosphoproteomic analysis and functional validation illuminated the phosphorylation of KAP1 at S473 as an important downstream BCR signaling event and a potential indicator for the success of ibrutinib treatment in CLL.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-21-0722
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 7
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    Abstract 5638: Total-sync ultra-content microscopic opto-biotinylation enables high-sensitivity hypothesis-free subcellular protein discovery
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5638-5638
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5638-5638
    Abstract: High-sensitivity hypothesis-free subcellular proteomics is challenging due to the limited sensitivity of mass spectrometry and the lack of amplification tools for proteins. Without such technology, it is not possible to discover proteins at specific locations of interest in cells or tissue samples. Here, we introduce a total-sync ultra-content microscopic system termed MicroscoopTM that integrates microscopy, optics, FPGA-based mechatronics, photochemistry, and deep learning or computer vision to enable high-content in situ photolabeling. MicroscoopTM photolabels proteins at user defined regions of interests (ROIs) under a microscope utilizing directed photochemistry in one field of view (FOV) at a time for tens of thousands of FOVs with similar morphological features. With this platform, we are able to photolabel proteins with biotin probes in cellular organelles, granules or cell-cell contact surfaces with a high precision at nanoscale resolution, and obtain sufficient amount of biotinylated proteins for mass spectrometry. We made a robust demonstration in the proteome mapping of human cellular nucleus from single-shot experiment to & gt;1000 nuclear protein identification with & gt; 90% specificity. Further data analysis revealed identification of a hundred of low protein copy number proteins and a high coverage of nuclear complexes. In proteome mapping of the nucleolus, we ranked proteins by order of abundance and revealed that 97 out of the top 100 proteins were annotated as nucleolar proteins. Unexpectedly, in mapping the stress granule (SG) proteome, a relatively low SG specificity (74%) were found in the top 50 abundant proteins, therefore we further characterize the proteins that have no prior SG annotation by immunostaining. Nine out of the thirteen unexplored proteins including PDLIM7, EIF3CL, YWHAE, RPSA, UGDH, DDX17, ANLN, PSMA6, and MCM2 were found to have SG patterns and co-localized with SG marker (G3BP1), raising our top 50 SG specificity to up to 92%. Together, our total-sync ultra-content microscopic platform enables hypothesis-free, de novo subcellular proteome mapping at user defined ROIs with high sensitivity and specificity, thereby broadly benefits the cell biology field in finding novel proteins or biomarkers. Citation Format: Jung-Chi Liao, Chih-Wei Chang, Yi-De Chen, Chantal Hoi Yin Cheung, Chia-Wen Chung, Hsiao-Jen Chang, Yong-Da Sie, You-Pi Liu, Yu-Chih Lin, Hsiang-Ju Kai, Weng Man Chong, Hsin-Yi Wu. Total-sync ultra-content microscopic opto-biotinylation enables high-sensitivity hypothesis-free subcellular protein discovery. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5638.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-5638
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 8
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    Abstract 4718: Inositol polyphosphate 4-phosphatase II activates PI3K/SGK3 signaling to promote proliferation of human melanoma cells
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4718-4718
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4718-4718
    Abstract: Inositol polyphosphate 4-phosphatase type II (INPP4B) inhibits phosphatidylinositol 3-kinase (PI3K)/Akt signaling and is emerging as a tumor suppressor in a variety of tissues. Here we report that, conversely, it functions as an oncogenic regulator in human melanoma through activating PI3K/SGK3 signaling. While it was upregulated in a subset of melanomas, knockdown of INPP4B inhibited melanoma cell proliferation in vitro, and retarded melanoma growth in a xenograft model. In contrast, overexpression of INPP4B resulted in increased proliferation and anchorage-independent growth of melanocytes. Strikingly, INPP4B did not impinge on activation of Akt in melanocytic cells. Instead, it promoted PI3K/SGK3 signaling, in that INPP4B knockdown inhibited, whereas overexpression of INPP4B enhanced, activation of SGK3. Indeed, the effect of INPP4B on melanocytic cell proliferation was due to enhanced activation of SGK3, as co-introduction of an active form of SGK3 rescued melanocytes and melanoma cells from inhibition of proliferation triggered by INPP4B knockdown, and knockdown of SGK3 abolished enhancement in cell proliferation resulting from INPP4B overexpression. Upregulation of INPP4B appeared largely due to downregulation of microRNA-494 (miR-494) and/or miR-599 as a result of gene copy number reduction in melanoma cells. Collectively, these results reveal that INPP4B upregulation mediated by loss of miR-494 and/or miR-599 promotes melanoma cell proliferation through activation of PI3K/SGK3 signaling, and suggest that the role of INPP4B in the pathogenesis of cancers of different origins needs to be defined discretely. Citation Format: Chen Chen Jiang, Meng Na Chi, Su Tang Guo, James S. Wilmott, Xiang Yun Guo, Xu Guang Yan, Chun Yan Wang, Xiao Ying Liu, Lei Jin, Hsin-Yi Tseng, Amanda Croft, Hubert Hondermarck, Tao Liu, Richard A. Scolyer, Xu Dong Zhang. Inositol polyphosphate 4-phosphatase II activates PI3K/SGK3 signaling to promote proliferation of human melanoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4718. doi:10.1158/1538-7445.AM2015-4718
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-4718
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 9
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    Abstract 6702: The clinical characteristics and outcomes of NSCLC patients with genomic alterations detected by blood-based NGS ctDNA assay
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6702-6702
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6702-6702
    Abstract: Background: The Blood First Assay Screening Trial (BFAST) (NCT03178552) is a prospective study screening for actionable genetic alterations using NGS of ctDNA among patients with treatment-naive advanced or metastatic NSCLC. We aimed to perform a more systematic investigation of genomic alterations in Asia/Taiwan NSCLC patients through the BFAST database at NTUH. Materials and Methods: There was a total of 269 patients enrolled and receiving FoundationOne Liquid Companion Diagnostic (F1LCDx) assay at cancer diagnosis between Feb, 2019 and Mar, 2022 in NTUH. The concordance of tissue-based genetic testing in the real-life clinical setting and the blood-based NGS testing in the clinical trial were analyzed. The co-occurrence of genomic alterations detected with blood-based NGS ctDNA assay were also interpreted. Results: A total of 206 patients (76.5%) detected driver mutations. Tissue-based genetic testing in the real-life clinical setting missed driver mutations in 67 (24.9%) patients with a sensitivity of 67.32%. Liquid NGS detected 38 (14%) patients with RET, KRAS, Met or ErbB2 mutations which were beyond the scope of current genetic testing in the clinical settings. Also, the F1LCDx assay detected more uncommon EGFR mutations than the Roche Cobas EGFR Mutation Test V2 (P & lt; 0.0001). Thirty-four (12.6%) patients had non-detected results in the F1LCDx assay which produced a sensitivity of 83.41%. By multivariate analysis, the predictors associated with discordant blood-based NGS ctDNA results were T stage (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.15-0.79, p = 0.012) and M stage (OR 0.21, 95% CI 0.09-0.49, p  & lt; 0.0001). The most common co-occurring mutations in the blood-based NGS ctDNA assay were TP53, DNMT3A, TET2, PIK3CA and CTNNB1. Among the EGFR mutant population, first-generation compared to third-generation TKI use (hazard ratio [HR] = 0.43, 95% CI 0.22-0.85, P=0.02) and co-occurring genomic alterations in TET2 (HR = 2.35, 95% CI 1.15-3.48, P=0.02) were associated with shorter progression free survival of EGFR TKIs treatment in multivariate analysis. Disease stage was the only factor associated with overall survival in the EGFR mutant population. Conclusion: NGS ctDNA analysis provided a more comprehensive genetic testing than conventional single gene testing kits. The lower stage which could imply lower or lack of ctDNA shedding into the blood was associated with a discordant result of the blood-based NGS ctDNA assay. Co-occurring mutations might have an impact on the treatment duration of EGFR-TKI. Citation Format: Hsin-Yi Wang, Chao-Chi Ho, Yen-Ting Lin, Wei-Yu Liao, Chung-Yu Chen, Jin-Yuan Shih, Chong-Jen Yu. The clinical characteristics and outcomes of NSCLC patients with genomic alterations detected by blood-based NGS ctDNA assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6702.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-6702
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 10
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    miR-103/107 Promote Metastasis of Colorectal Cancer by Targeting the Metastasis Suppressors DAPK and KLF4
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 14 ( 2012-07-15), p. 3631-3641
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 14 ( 2012-07-15), p. 3631-3641
    Abstract: Metastasis is the major cause of poor prognosis in colorectal cancer (CRC), and increasing evidence supports the contribution of miRNAs to cancer progression. Here, we found that high expression of miR-103 and miR-107 (miR-103/107) was associated with metastasis potential of CRC cell lines and poor prognosis in patients with CRC. We showed that miR-103/107 targeted the known metastasis suppressors death-associated protein kinase (DAPK) and Krüppel-like factor 4 (KLF4) in CRC cells, resulting in increased cell motility and cell–matrix adhesion and decreased cell–cell adhesion and epithelial marker expression. miR-103/107 expression was increased in the presence of hypoxia, thereby potentiating DAPK and KLF4 downregulation and hypoxia-induced motility and invasiveness. In mouse models of CRC, miR-103/107 overexpression potentiated local invasion and liver metastasis effects, which were suppressed by reexpression of DAPK or KLF4. miR-103/107–mediated downregulation of DAPK and KLF4 also enabled the colonization of CRC cells at a metastatic site. Clinically, the signature of a miR-103/107 high, DAPK low, and KLF4 low expression profile correlated with the extent of lymph node and distant metastasis in patients with CRC and served as a prognostic marker for metastasis recurrence and poor survival. Our findings therefore indicate that miR-103/107–mediated repression of DAPK and KLF4 promotes metastasis in CRC, and this regulatory circuit may contribute in part to hypoxia-stimulated tumor metastasis. Strategies that disrupt this regulation might be developed to block CRC metastasis. Cancer Res; 72(14); 3631–41. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-12-0667
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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