Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-1986
Ying Yan, Lepakshe S V Madduri, Nichole D. Brandquist, C. Palanivel, Sumin Zhou, C. Enke, M. Ouellette
{"title":"Abstract 1986: p53/FBXL20 axis negatively regulates the protein stability of PR55α, a PP2A regulatory subunit","authors":"Ying Yan, Lepakshe S V Madduri, Nichole D. Brandquist, C. Palanivel, Sumin Zhou, C. Enke, M. Ouellette","doi":"10.1158/1538-7445.AM2021-1986","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1986","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74659241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2012
G. Pezzicoli, D. Lovero, M. Tucci, C. Porta, Francesco Mannavola
{"title":"Abstract 2012:In vitrovalidation of tumor-derived large extracellular vesicles isolation and characterization as suitable tool for liquid biopsy","authors":"G. Pezzicoli, D. Lovero, M. Tucci, C. Porta, Francesco Mannavola","doi":"10.1158/1538-7445.AM2021-2012","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2012","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74670958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2507
Janine Deblasi, Aimee Falzone, G. DeNicola
Lung cancer is responsible for the most cancer-related deaths worldwide. Within the most prominent histological subtype, non-small cell lung cancer (NSCLC), there is an unmet clinical need: lung adenocarcinomas (ADCs) driven by mutant KRAS. Within this subset of tumors, KRAS mutations co-occur with mutations in tumor suppressor genes including TP53 and the redox regulator KEAP1. KEAP1 is the negative regulator of transcription factor NRF2, which directs the antioxidant response and multiple facets of metabolism. In NSCLC, alterations in the KEAP1-NRF2 circuit result in constitutive NRF2 activation and are often associated with resistance to therapy and poor outcomes in patients. While NRF2 hyperactivation has been associated with tumor progression, our lab's recent findings suggest that this may be context-dependent, and that too much NRF2 activation may be detrimental. To study the role of NRF2 hyperactivation on tumor progression, we have utilized KRAS mutant genetically engineered mouse models of NSCLC harboring TP53 deletion. These studies are based on our lab's finding that the homozygous KEAP1R554Q loss-of-function mutation decreases tumor size in a Kras mutant, Trp53-deficient (KP) lung ADC model (Kang et al. 2019 eLife). In parallel to these studies, we have also developed a conditional murine allele of the NRF2D29H mutation found in human NSCLC to serve as a secondary model of NRF2 hyperactivation in the KP mouse (KPN). Consistent with our homozygous KEAP1 mutant model (KPKK), we found that KPN mice demonstrated constitutive NRF2 activation, as observed by increased immunohistochemical staining of canonical NRF2 target, NQO1. This degree of NRF2 activation in KPN mice was slightly lower than that of KPKK mice, suggesting that the KPN mouse is an intermediate model of NRF2 activation. Supportingly, we also found that KPN mice had decreased tumor burden, although not to the same extent as KPKK mice. Interestingly, our heterozygous KEAP1 mutant model (KPK) demonstrates only modest NRF2 activation but did not exhibit decreased tumor burden. Importantly, analyses of tumor number suggested that KPKK and KPN tumors are impaired in tumor progression, rather than initiation. KPKK and KPN tumors also exhibited lower proliferative indices when compared to KP mice, in correspondence with their reduced tumor burden. Collectively, these results suggest that there may be a threshold for NRF2 activation to block tumor progression in the KP model. Current studies are focused on determining whether this impediment to tumor burden is NRF2-dependent, and what NRF2-dependent mechanisms may impair tumor progression. Importantly, these studies may help identify whether a threshold for NRF2 hyperactivation to promote or block tumor progression exists, and if this can be therapeutically exploited in patients with KRAS mutant, TP53-deficient lung tumors. Citation Format: Janine M. DeBlasi, Aimee Falzone, Gina M. DeNicola. Does a threshold exist for NRF2 hyperacti
肺癌是全世界癌症相关死亡人数最多的疾病。在最突出的组织学亚型非小细胞肺癌(NSCLC)中，有一个未满足的临床需求:由突变KRAS驱动的肺腺癌(adc)。在这一肿瘤亚群中，KRAS突变与肿瘤抑制基因(包括TP53和氧化还原调节因子KEAP1)的突变共同发生。KEAP1是转录因子NRF2的负调控因子，调控抗氧化反应和代谢的多个方面。在非小细胞肺癌中，KEAP1-NRF2回路的改变导致构成性NRF2激活，并且通常与患者的治疗抵抗和不良预后相关。虽然NRF2过度激活与肿瘤进展有关，但我们实验室最近的研究结果表明，这可能与环境有关，过多的NRF2激活可能是有害的。为了研究NRF2过度激活在肿瘤进展中的作用，我们利用KRAS突变基因工程的非小细胞肺癌小鼠模型携带TP53缺失。这些研究基于我们实验室的发现，即在Kras突变体trp53缺陷(KP)肺ADC模型中，纯合子KEAP1R554Q功能缺失突变会降低肿瘤大小(Kang et al. 2019 eLife)。与这些研究并行，我们还开发了人类NSCLC中发现的NRF2D29H突变的条件小鼠等位基因，作为KP小鼠(KPN) NRF2过度激活的次要模型。与我们的KEAP1纯合子突变模型(KPKK)一致，我们发现KPN小鼠表现出组成性NRF2激活，通过增加典型NRF2靶点NQO1的免疫组织化学染色观察到。KPN小鼠的NRF2激活程度略低于KPKK小鼠，提示KPN小鼠是NRF2激活的中间模型。支持的是，我们还发现KPN小鼠减轻了肿瘤负荷，尽管程度与KPKK小鼠不同。有趣的是，我们的杂合KEAP1突变模型(KPK)仅显示适度的NRF2激活，但没有显示出肿瘤负荷的减少。重要的是，对肿瘤数量的分析表明，KPKK和KPN肿瘤在肿瘤进展中受损，而不是在肿瘤开始时受损。与KP小鼠相比，KPKK和KPN肿瘤也表现出较低的增殖指数，这与它们减轻的肿瘤负担相一致。总的来说，这些结果表明，在KP模型中，NRF2激活可能存在一个阈值，以阻止肿瘤进展。目前的研究主要集中在确定这种对肿瘤负荷的阻碍是否依赖于nrf2，以及nrf2依赖的机制可能损害肿瘤进展。重要的是，这些研究可能有助于确定NRF2过度激活是否存在促进或阻断肿瘤进展的阈值，以及是否可以在KRAS突变、tp53缺失的肺肿瘤患者中进行治疗。引用格式:Janine M. DeBlasi, Aimee Falzone, Gina M. DeNicola。在KRAS突变体、缺乏tp53的非小细胞肺癌中，是否存在NRF2过度激活以阻止肿瘤进展的阈值[摘要]?见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):第2507期。
{"title":"Abstract 2507: Does a threshold exist for NRF2 hyperactivation to block tumor progression in KRAS mutant, TP53-deficient NSCLC","authors":"Janine Deblasi, Aimee Falzone, G. DeNicola","doi":"10.1158/1538-7445.AM2021-2507","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2507","url":null,"abstract":"Lung cancer is responsible for the most cancer-related deaths worldwide. Within the most prominent histological subtype, non-small cell lung cancer (NSCLC), there is an unmet clinical need: lung adenocarcinomas (ADCs) driven by mutant KRAS. Within this subset of tumors, KRAS mutations co-occur with mutations in tumor suppressor genes including TP53 and the redox regulator KEAP1. KEAP1 is the negative regulator of transcription factor NRF2, which directs the antioxidant response and multiple facets of metabolism. In NSCLC, alterations in the KEAP1-NRF2 circuit result in constitutive NRF2 activation and are often associated with resistance to therapy and poor outcomes in patients. While NRF2 hyperactivation has been associated with tumor progression, our lab's recent findings suggest that this may be context-dependent, and that too much NRF2 activation may be detrimental. To study the role of NRF2 hyperactivation on tumor progression, we have utilized KRAS mutant genetically engineered mouse models of NSCLC harboring TP53 deletion. These studies are based on our lab's finding that the homozygous KEAP1R554Q loss-of-function mutation decreases tumor size in a Kras mutant, Trp53-deficient (KP) lung ADC model (Kang et al. 2019 eLife). In parallel to these studies, we have also developed a conditional murine allele of the NRF2D29H mutation found in human NSCLC to serve as a secondary model of NRF2 hyperactivation in the KP mouse (KPN). Consistent with our homozygous KEAP1 mutant model (KPKK), we found that KPN mice demonstrated constitutive NRF2 activation, as observed by increased immunohistochemical staining of canonical NRF2 target, NQO1. This degree of NRF2 activation in KPN mice was slightly lower than that of KPKK mice, suggesting that the KPN mouse is an intermediate model of NRF2 activation. Supportingly, we also found that KPN mice had decreased tumor burden, although not to the same extent as KPKK mice. Interestingly, our heterozygous KEAP1 mutant model (KPK) demonstrates only modest NRF2 activation but did not exhibit decreased tumor burden. Importantly, analyses of tumor number suggested that KPKK and KPN tumors are impaired in tumor progression, rather than initiation. KPKK and KPN tumors also exhibited lower proliferative indices when compared to KP mice, in correspondence with their reduced tumor burden. Collectively, these results suggest that there may be a threshold for NRF2 activation to block tumor progression in the KP model. Current studies are focused on determining whether this impediment to tumor burden is NRF2-dependent, and what NRF2-dependent mechanisms may impair tumor progression. Importantly, these studies may help identify whether a threshold for NRF2 hyperactivation to promote or block tumor progression exists, and if this can be therapeutically exploited in patients with KRAS mutant, TP53-deficient lung tumors. Citation Format: Janine M. DeBlasi, Aimee Falzone, Gina M. DeNicola. Does a threshold exist for NRF2 hyperacti","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74886016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2481
K. Durinck, Mark W. Zimmerman, Nina Weichert-Leahey, J. Dewyn, W. V. Loocke, C. Nunes, A. Beckers, Bieke Decaesteker, P. Volders, C. V. Neste, B. Cheung, Daniel R. Carter, T. Look, G. Marshall, K. D. Preter, Adam D. Durbin, F. Speleman
{"title":"Abstract 2481: Time-resolved transcriptome analysis of murine TH-MYCN driven neuroblastoma identifies MEIS2 as early initiating factor and novel core gene regulatory circuitry constituent","authors":"K. Durinck, Mark W. Zimmerman, Nina Weichert-Leahey, J. Dewyn, W. V. Loocke, C. Nunes, A. Beckers, Bieke Decaesteker, P. Volders, C. V. Neste, B. Cheung, Daniel R. Carter, T. Look, G. Marshall, K. D. Preter, Adam D. Durbin, F. Speleman","doi":"10.1158/1538-7445.AM2021-2481","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2481","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"133 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75696371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2185
Tomonori Hirano, N. Kakiuchi, Y. Takeuchi, T. Nishimura, T. Masui, Sachiko Minamiguhi, H. Haga, K. Chiba, Hiroko Tanaka, Y. Shiraishi, S. Miyano, Uza Norimitsu, Y. Kodama, H. Seno, S. Ogawa
{"title":"Abstract 2185: Genetic analysis of metachronous pancreatic cancers","authors":"Tomonori Hirano, N. Kakiuchi, Y. Takeuchi, T. Nishimura, T. Masui, Sachiko Minamiguhi, H. Haga, K. Chiba, Hiroko Tanaka, Y. Shiraishi, S. Miyano, Uza Norimitsu, Y. Kodama, H. Seno, S. Ogawa","doi":"10.1158/1538-7445.AM2021-2185","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2185","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74040124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-1962
S. Wiley, Yongwei Su, Y. Ge
{"title":"Abstract 1962: Voruciclib, a CDK9 inhibitor, downregulates MYC and inhibits proliferation of KRAS mutant cancers in preclinical models","authors":"S. Wiley, Yongwei Su, Y. Ge","doi":"10.1158/1538-7445.AM2021-1962","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-1962","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75106498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-91
C. Ghezzi, R. Damoiseaux, P. M. Clark
Squamous cell lung cancer (SqCLC) represents 30% of all cases of non-small cell lung cancer. Despite the prevalence of SqCLC, there are few molecularly targeted therapies for SqCLC patients. There is an urgent need for new approaches in this area. SqCLC cells consume elevated levels of glucose and are highly dependent on glucose consumption for their survival. Targeting glucose consumption may be a valuable therapeutic strategy in SqCLC but is challenged by the fact that glucose consumption is critical for vital organs. Our ability to selectively target glucose consumption in SqCLC is limited by an incomplete understanding of the shared and distinct mechanisms through which SqCLC and healthy cells drive glucose consumption. We recently developed and validated a high-throughput glucose consumption assay that serves as a platform technology for identifying new proteins and pathways that drive glucose consumption in cancerous and healthy cells. In this project, we screened H520, SK-MES-1, and H596 SqCLC cell lines against 3555 bioactive small molecules including a library of kinase inhibitors and FDA-approved drugs, and measured glucose consumption 24 hours after drug treatment. We discovered and validated 62 compounds that decreased glucose consumption per cell by >50% in at least one cell line. From this list, we searched for compounds that decreased glucose consumption in all three cell lines, by >70% in at least one cell line, and with an EC50 value Pacritinib reduces glucose consumption in all three SqCLC cell lines with an EC50 value of 1.2 µM in cell culture and blocks glucose consumption in cell line xenografts in vivo without affecting glucose consumption in healthy tissues. In the SqCLC cell lines, Pacritinib decreases protein levels of Hexokinase 1 and Hexokinase 2 as well as hexokinase activity as measured by a FRET-based glucose sensor. Hexokinase 1 overexpression in the SqCLC cell lines blocks Pacritinib from inhibiting glucose consumption. Pacritinib targets JAK2, TYK2, FLT3, and additional kinases at low nanomolar concentrations in vitro. Additional small molecule inhibitors of JAK2 and TYK2 had no effect on SqCLC glucose consumption. However additional inhibitors of FLT3 blocked glucose consumption in all three SqCLC cell lines. FLT3 overexpression increased SqCLC glucose consumption and blocked Pacritinib from inhibiting glucose consumption. In conclusion, using our high-throughput technology, we discovered that FLT3 is a selective and targetable driver of glucose consumption in SqCLC. Our data suggest that FLT3 activates glucose consumption by increasing Hexokinase 1 levels. Citation Format: Chiara Ghezzi, Robert Damoiseaux, Peter M. Clark. FLT3 is a major driver of glucose consumption in squamous cell lung cancer [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 91.
鳞状细胞肺癌(SqCLC)占所有非小细胞肺癌的30%。尽管SqCLC很普遍，但针对SqCLC患者的分子靶向治疗却很少。在这一领域迫切需要新的方法。SqCLC细胞消耗高水平的葡萄糖，其生存高度依赖葡萄糖消耗。靶向葡萄糖消耗可能是SqCLC的一种有价值的治疗策略，但葡萄糖消耗对重要器官至关重要，这一事实受到了挑战。我们选择性靶向SqCLC中葡萄糖消耗的能力受到对SqCLC和健康细胞驱动葡萄糖消耗的共同和独特机制的不完全理解的限制。我们最近开发并验证了一种高通量葡萄糖消耗测定，作为识别癌症和健康细胞中驱动葡萄糖消耗的新蛋白质和途径的平台技术。在本项目中，我们对H520、SK-MES-1和H596 SqCLC细胞系进行了3555种生物活性小分子的筛选，包括激酶抑制剂和fda批准的药物库，并测量了药物治疗后24小时的葡萄糖消耗。我们发现并验证了62种化合物，这些化合物至少在一种细胞系中使每个细胞的葡萄糖消耗降低了50%以上。从这个列表中，我们搜索了在所有三种细胞系中降低葡萄糖消耗的化合物，至少在一种细胞系中降低了>70%，并且具有EC50值Pacritinib在细胞培养中降低了所有三种SqCLC细胞系的葡萄糖消耗，EC50值为1.2µM，并且在不影响健康组织中葡萄糖消耗的情况下阻断了细胞系异种移植体内的葡萄糖消耗。在SqCLC细胞系中，Pacritinib降低了己糖激酶1和己糖激酶2的蛋白水平以及己糖激酶活性，这是由基于fret的葡萄糖传感器测量的。己糖激酶1在SqCLC细胞系中的过表达阻断了Pacritinib抑制葡萄糖消耗的作用。Pacritinib在体外以低纳摩尔浓度靶向JAK2, TYK2, FLT3和其他激酶。JAK2和TYK2的其他小分子抑制剂对SqCLC的葡萄糖消耗没有影响。然而，FLT3抑制剂阻断了所有三种SqCLC细胞系的葡萄糖消耗。FLT3过表达增加SqCLC葡萄糖消耗，阻断Pacritinib抑制葡萄糖消耗的作用。总之，利用我们的高通量技术，我们发现FLT3是SqCLC中葡萄糖消耗的选择性和可靶向驱动因子。我们的数据表明FLT3通过增加己糖激酶1水平来激活葡萄糖消耗。引文格式:Chiara Ghezzi, Robert Damoiseaux, Peter M. Clark。FLT3是鳞状细胞肺癌中葡萄糖消耗的主要驱动因素[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):摘要第91期。
{"title":"Abstract 91: FLT3 is a major driver of glucose consumption in squamous cell lung cancer","authors":"C. Ghezzi, R. Damoiseaux, P. M. Clark","doi":"10.1158/1538-7445.AM2021-91","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-91","url":null,"abstract":"Squamous cell lung cancer (SqCLC) represents 30% of all cases of non-small cell lung cancer. Despite the prevalence of SqCLC, there are few molecularly targeted therapies for SqCLC patients. There is an urgent need for new approaches in this area. SqCLC cells consume elevated levels of glucose and are highly dependent on glucose consumption for their survival. Targeting glucose consumption may be a valuable therapeutic strategy in SqCLC but is challenged by the fact that glucose consumption is critical for vital organs. Our ability to selectively target glucose consumption in SqCLC is limited by an incomplete understanding of the shared and distinct mechanisms through which SqCLC and healthy cells drive glucose consumption. We recently developed and validated a high-throughput glucose consumption assay that serves as a platform technology for identifying new proteins and pathways that drive glucose consumption in cancerous and healthy cells. In this project, we screened H520, SK-MES-1, and H596 SqCLC cell lines against 3555 bioactive small molecules including a library of kinase inhibitors and FDA-approved drugs, and measured glucose consumption 24 hours after drug treatment. We discovered and validated 62 compounds that decreased glucose consumption per cell by >50% in at least one cell line. From this list, we searched for compounds that decreased glucose consumption in all three cell lines, by >70% in at least one cell line, and with an EC50 value Pacritinib reduces glucose consumption in all three SqCLC cell lines with an EC50 value of 1.2 µM in cell culture and blocks glucose consumption in cell line xenografts in vivo without affecting glucose consumption in healthy tissues. In the SqCLC cell lines, Pacritinib decreases protein levels of Hexokinase 1 and Hexokinase 2 as well as hexokinase activity as measured by a FRET-based glucose sensor. Hexokinase 1 overexpression in the SqCLC cell lines blocks Pacritinib from inhibiting glucose consumption. Pacritinib targets JAK2, TYK2, FLT3, and additional kinases at low nanomolar concentrations in vitro. Additional small molecule inhibitors of JAK2 and TYK2 had no effect on SqCLC glucose consumption. However additional inhibitors of FLT3 blocked glucose consumption in all three SqCLC cell lines. FLT3 overexpression increased SqCLC glucose consumption and blocked Pacritinib from inhibiting glucose consumption. In conclusion, using our high-throughput technology, we discovered that FLT3 is a selective and targetable driver of glucose consumption in SqCLC. Our data suggest that FLT3 activates glucose consumption by increasing Hexokinase 1 levels. Citation Format: Chiara Ghezzi, Robert Damoiseaux, Peter M. Clark. FLT3 is a major driver of glucose consumption in squamous cell lung cancer [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 91.","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75001433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2165
L. F. Leal, M. S. Gonçalves, Luciane Sussuchi da Silva, M. A. Lima, M.B.P.P. Olveira, Shen Yin, H. N. Bastos, P. Marchi, Josiane M Dias, F. Carneiro, C. Moura, Vinicius Duval Silva, Ignacio I. Witsuba, Xie Yang, R. Reis
{"title":"Abstract 2165: Reproducibility of a 12-gene panel and development of user-friendly nomogram-based calculator for clinical management of surgically resected non-small cell lung cancer patients","authors":"L. F. Leal, M. S. Gonçalves, Luciane Sussuchi da Silva, M. A. Lima, M.B.P.P. Olveira, Shen Yin, H. N. Bastos, P. Marchi, Josiane M Dias, F. Carneiro, C. Moura, Vinicius Duval Silva, Ignacio I. Witsuba, Xie Yang, R. Reis","doi":"10.1158/1538-7445.AM2021-2165","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2165","url":null,"abstract":"","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"76 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75140734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2360
Victoria A. Stark, Vignesh Viswanathan, C. Facey, Lynn M. Opdenaker, B. Boman
Our research goal is to discover the molecular mechanisms behind tumor heterogeneity in CRC. We previously showed that CRCs contain multiple subpopulations of cancer stem cells (CSCs) which may explain the occurrence tumor heterogeneity and resistance to treatment. To determine how CSC sub-populations might arise, we are studying miRNA expression in CRC SCs. MicroRNAs are known to regulate SC phenotype and are found to be dysregulated in many cancers. Hypothesis: Tumor heterogeneity results from existence of multiple CSC subpopulations that are regulated by distinct miRNAs. Accordingly, we are using bioinformatics and miRNA profiling to identify miRNAs that target SC genes in CRCs. Indeed, our miRNA expression profiling of normal and malignant ALDH+ human colonic SCs showed that miRNA92a targets the SC gene LRIG1 and upregulation of miRNA92a leads to decreased LRIG1 expression. We also discovered that miRNA23b targets the SC gene LGR5 and miRNA23b is upregulated in ALDH+ CSCs. We have identified several other candidate miRNAs that are predicted to target CD166, ALDH1A1, BMI1, LRG5, and LRIG1 SC genes. We are currently in the process of validating whether these miRNAs contribute to emergence of specific CSC sub-populations in CRCs. Thus, identifying miRNAs that regulate CSC subpopulations should provide new strategies to modulate CSC composition in order to sensitize tumors to treatments. Citation Format: Victoria A. Stark, Vignesh Viswanathan, Caroline O. Facey, Lynn M. Opdenaker, Bruce M. Boman. Identifying differentially expressed miRNAs in CRC stem cell subpopulations [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 2360.
我们的研究目标是发现CRC中肿瘤异质性背后的分子机制。我们之前的研究表明，crc包含癌症干细胞(CSCs)的多个亚群，这可能解释了肿瘤异质性和治疗耐药性的发生。为了确定CSC亚群是如何产生的，我们正在研究CRC sc中miRNA的表达。已知microrna调节SC表型，并在许多癌症中被发现失调。假设:肿瘤异质性源于多个CSC亚群的存在，这些亚群受不同的mirna调节。因此，我们正在使用生物信息学和miRNA分析来鉴定靶向crc中SC基因的miRNA。事实上，我们的正常和恶性ALDH+人结肠SCs的miRNA表达谱显示，miRNA92a靶向SC基因LRIG1, miRNA92a的上调导致LRIG1表达降低。我们还发现miRNA23b靶向SC基因LGR5，并且miRNA23b在ALDH+ CSCs中上调。我们已经确定了其他几个候选mirna，它们被预测靶向CD166、ALDH1A1、BMI1、LRG5和LRIG1 SC基因。我们目前正在验证这些mirna是否有助于crc中特定CSC亚群的出现。因此，鉴定调节CSC亚群的mirna应该为调节CSC组成提供新的策略，从而使肿瘤对治疗敏感。引文格式:Victoria A. Stark, Vignesh Viswanathan, Caroline O. Facey, Lynn M. Opdenaker, Bruce M. Boman。鉴别结直肠癌干细胞亚群中差异表达的mirna[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):摘要nr 2360。
{"title":"Abstract 2360: Identifying differentially expressed miRNAs in CRC stem cell subpopulations","authors":"Victoria A. Stark, Vignesh Viswanathan, C. Facey, Lynn M. Opdenaker, B. Boman","doi":"10.1158/1538-7445.AM2021-2360","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2360","url":null,"abstract":"Our research goal is to discover the molecular mechanisms behind tumor heterogeneity in CRC. We previously showed that CRCs contain multiple subpopulations of cancer stem cells (CSCs) which may explain the occurrence tumor heterogeneity and resistance to treatment. To determine how CSC sub-populations might arise, we are studying miRNA expression in CRC SCs. MicroRNAs are known to regulate SC phenotype and are found to be dysregulated in many cancers. Hypothesis: Tumor heterogeneity results from existence of multiple CSC subpopulations that are regulated by distinct miRNAs. Accordingly, we are using bioinformatics and miRNA profiling to identify miRNAs that target SC genes in CRCs. Indeed, our miRNA expression profiling of normal and malignant ALDH+ human colonic SCs showed that miRNA92a targets the SC gene LRIG1 and upregulation of miRNA92a leads to decreased LRIG1 expression. We also discovered that miRNA23b targets the SC gene LGR5 and miRNA23b is upregulated in ALDH+ CSCs. We have identified several other candidate miRNAs that are predicted to target CD166, ALDH1A1, BMI1, LRG5, and LRIG1 SC genes. We are currently in the process of validating whether these miRNAs contribute to emergence of specific CSC sub-populations in CRCs. Thus, identifying miRNAs that regulate CSC subpopulations should provide new strategies to modulate CSC composition in order to sensitize tumors to treatments. Citation Format: Victoria A. Stark, Vignesh Viswanathan, Caroline O. Facey, Lynn M. Opdenaker, Bruce M. Boman. Identifying differentially expressed miRNAs in CRC stem cell subpopulations [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 2360.","PeriodicalId":18754,"journal":{"name":"Molecular and Cellular Biology / Genetics","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77670990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：