Silvia Fenoglio, Aileen M. Cristo, James Tepper, T. Teng, Samuel R. Meier, Ashley H Choi, Hongxiang Zhang, Shan-Chuan Zhao, Shangtao Liu, Leanne G. Ahronian, Daniel Aird, Nikitha Das, Yi Yu, R. T. Sjin, Jannik N Andersen, A. Huang, Fang Li, Xuewen Pan
{"title":"Abstract P183: CRISPR screens identify sensitizers to trametinib in KRAS mutant cancer cell lines","authors":"Silvia Fenoglio, Aileen M. Cristo, James Tepper, T. Teng, Samuel R. Meier, Ashley H Choi, Hongxiang Zhang, Shan-Chuan Zhao, Shangtao Liu, Leanne G. Ahronian, Daniel Aird, Nikitha Das, Yi Yu, R. T. Sjin, Jannik N Andersen, A. Huang, Fang Li, Xuewen Pan","doi":"10.1158/1535-7163.targ-21-p183","DOIUrl":"https://doi.org/10.1158/1535-7163.targ-21-p183","url":null,"abstract":"","PeriodicalId":20348,"journal":{"name":"Poster Presentations - Proffered Abstracts","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91230672","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}
D. Thakkar, Shalini Paliwal, S. Kar, N. Gandhi, Konrad H. Paszkiewicz, P. Ingram, J. Boyd-Kirkup
{"title":"Abstract P197: An anti-HER3 antibody, HMBD-001, that uniquely binds to and blocks the HER3 heterodimerization interface, shows superior tumor growth inhibition in biomarker-defined preclinical cancer models including NRG1-fusion driven cancers","authors":"D. Thakkar, Shalini Paliwal, S. Kar, N. Gandhi, Konrad H. Paszkiewicz, P. Ingram, J. Boyd-Kirkup","doi":"10.1158/1535-7163.targ-21-p197","DOIUrl":"https://doi.org/10.1158/1535-7163.targ-21-p197","url":null,"abstract":"","PeriodicalId":20348,"journal":{"name":"Poster Presentations - Proffered Abstracts","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83095605","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}
Tyler A. Cunningham, J. Ho, P. Manara, Stephen Lee, J. Schatz
{"title":"Abstract P028: Proteomic approaches define rocaglates as translation remodelers with multiple protein targets","authors":"Tyler A. Cunningham, J. Ho, P. Manara, Stephen Lee, J. Schatz","doi":"10.1158/1535-7163.targ-21-p028","DOIUrl":"https://doi.org/10.1158/1535-7163.targ-21-p028","url":null,"abstract":"Intro: Deregulated protein synthesis is a common trait across solid and hematologic malignancies and an attractive target for cancer therapy. Rocaglates compounds that inhibit eukaryotic initiation factor 4A1 (eIF4A1), the essential DEAD-box RNA helicase that resolves mRNA 5'UTR secondary structures during cap-dependent translation initiation. Rocaglates' unique mechanism of action causes sequence-selective mRNA binding by eIF4A1, clamping the inactive helicase onto the transcript. This suppresses translation globally and affects many oncogenic and pro-survival transcripts in particular. Zotatifin, the first-in class synthetic rocaglate, is currently in Phase I clinical trials for the treatment of solid tumors and as an antiviral against SARS-CoV2. Currently, eIF4A1 and DDX3 are the only reported targets of rocaglate-mediated RNA clamping. Employing unbiased proteomic approaches, we have discovered that rocaglates, thought to act as pure eIF4A/translation inhibitors, extensively remodel the translation machinery and translatome. Additionally, mass-spec interrogation for proteins interacting with specific RNA sequences reveals novel targets of rocaglate-mediated, sequence-specific RNA clamping. Methods: We conducted original mass-spectrometry analyses of translational reprogramming by rocaglates. TMT-pSILAC assessed acute changes in protein production, while MATRIX, which captures high-resolution profiles of the translation machinery, revealed translation factors that drive reprogramming in response to rocaglate exposure. We validated results biochemically, in cellulo, and in vivo using patient-derived xenograft (PDX) mouse models. To probe existing and novel rocaglate RNA-clamping targets, we developed unbiased “clampome” assays - in cellulo protein-RNA-pull downs followed by mass-spec analysis of proteins with increased binding to RNA in the presence of rocaglates. Results: We find rocaglates, including zotatifin, have effects far more complex than simple “translational inhibition” as currently defined. Indeed, translatome analysis by TMT-pSILAC revealed myriad up-regulated proteins that drive hitherto unrecognized cytotoxic mechanisms. The GEF-H1 guanine exchange factor, for example, drives anti-survival RHOA/JNK activation, suggesting novel candidate biomarkers of rocaglate clinical outcomes. Translation-machinery analysis by MATRIX identifed rocaglate-induced dependence on specific translation factors including eEF1ϵ1 that drive remodeling. Novel rocaglate RNA-binding targets revealed by clampome studies remain under detailed evaluation as mediators of drug activities. Discussion: Our original proteome-level interrogation revealed that the complete cellular response to these historical “translation inhibitors” is mediated by comprehensive translational landscape remodeling. Effects on a broader suite of RNA binding proteins than eIF4A1 alone we suggest mediate the potent antitumor activities of these unique compounds, elucidation of which per","PeriodicalId":20348,"journal":{"name":"Poster Presentations - Proffered Abstracts","volume":"2013 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87896294","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}
{"title":"Abstract P145: The RNA helicase EIF4A is a therapeutic vulnerability in triple-negative breast cancer","authors":"N. Zhao, J. Rosen","doi":"10.1158/1535-7163.targ-21-p145","DOIUrl":"https://doi.org/10.1158/1535-7163.targ-21-p145","url":null,"abstract":"","PeriodicalId":20348,"journal":{"name":"Poster Presentations - Proffered Abstracts","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77404103","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}
M. Pfeifer, Jonathan S. Brammeld, S. Price, Matthew J. Martin, H. Thorpe, A. Bornot, Ercia Banks, N. Guan, S. Dunn, Maria Lisa Guerriero, Daniel O'Neill, J. Pilling, Davide Gianni, J. Brownell, Paul D. Smith, Ultan McDermott
{"title":"Abstract P066: Gain and loss of function genome-wide CRISPR screens identify Hippo signalling as an important driver of resistance in EGFR mutant lung cancer","authors":"M. Pfeifer, Jonathan S. Brammeld, S. Price, Matthew J. Martin, H. Thorpe, A. Bornot, Ercia Banks, N. Guan, S. Dunn, Maria Lisa Guerriero, Daniel O'Neill, J. Pilling, Davide Gianni, J. Brownell, Paul D. Smith, Ultan McDermott","doi":"10.1158/1535-7163.targ-21-p066","DOIUrl":"https://doi.org/10.1158/1535-7163.targ-21-p066","url":null,"abstract":"","PeriodicalId":20348,"journal":{"name":"Poster Presentations - Proffered Abstracts","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88881948","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}
Michelle Lin, A. Nagaraja, D. Haria, Y. Katlinskaya, D. Ravichandar, Preston Williams, Roberta L Hannibal, T. DeSantis, B. Hwang, Michael Wilcoxon, T. Takeuchi, K. Dabbagh, P. Lal, H. Kiefel
{"title":"Abstract P260: Development and validation of a novel T-cell modulating, microbiome-based peptide for combination with immunotherapy","authors":"Michelle Lin, A. Nagaraja, D. Haria, Y. Katlinskaya, D. Ravichandar, Preston Williams, Roberta L Hannibal, T. DeSantis, B. Hwang, Michael Wilcoxon, T. Takeuchi, K. Dabbagh, P. Lal, H. Kiefel","doi":"10.1158/1535-7163.targ-21-p260","DOIUrl":"https://doi.org/10.1158/1535-7163.targ-21-p260","url":null,"abstract":"","PeriodicalId":20348,"journal":{"name":"Poster Presentations - Proffered Abstracts","volume":"251 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73372114","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}
J. Stenvang, N. L. Roest, P. M. Vestlev, B. Hansen
{"title":"Abstract P077: SCO-101 mediates re-sensitization of irinotecan (SN38) resistant colorectal cancer cells","authors":"J. Stenvang, N. L. Roest, P. M. Vestlev, B. Hansen","doi":"10.1158/1535-7163.targ-21-p077","DOIUrl":"https://doi.org/10.1158/1535-7163.targ-21-p077","url":null,"abstract":"","PeriodicalId":20348,"journal":{"name":"Poster Presentations - Proffered Abstracts","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75983223","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}
Susana Banerjee, B. Monk, E. Van Nieuwenhuysen, K. Moore, A. Oaknin, M. Fabbro, Nicoletta Columbo, D. O’Malley, R. Coleman, J. Pachter, A. Koustenis, Gloria Patrick, Lorna Leonard, R. Grisham
{"title":"Abstract P046: ENGOT-ov60/GOG3052/RAMP 201: A phase 2 study of VS-6766 (dual RAF/MEK inhibitor) alone and in combination with defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC)","authors":"Susana Banerjee, B. Monk, E. Van Nieuwenhuysen, K. Moore, A. Oaknin, M. Fabbro, Nicoletta Columbo, D. O’Malley, R. Coleman, J. Pachter, A. Koustenis, Gloria Patrick, Lorna Leonard, R. Grisham","doi":"10.1158/1535-7163.targ-21-p046","DOIUrl":"https://doi.org/10.1158/1535-7163.targ-21-p046","url":null,"abstract":"","PeriodicalId":20348,"journal":{"name":"Poster Presentations - Proffered Abstracts","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76166423","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}
M. Salkeni, G. Coyne, Jennifer Zlott, N. Takebe, N. Ma, L. Rubinstein, R. Piekarz, Jared C. Foster, Brandon Miller, R. Parchment, A. Naqash, A. Voth, J. Doroshow, A. Chen
{"title":"Abstract P049: Phase II trial of TRC102 (methoxyamine HCl) in combination with temozolomide (TMZ) in patients with advanced non-small cell lung cancer","authors":"M. Salkeni, G. Coyne, Jennifer Zlott, N. Takebe, N. Ma, L. Rubinstein, R. Piekarz, Jared C. Foster, Brandon Miller, R. Parchment, A. Naqash, A. Voth, J. Doroshow, A. Chen","doi":"10.1158/1535-7163.targ-21-p049","DOIUrl":"https://doi.org/10.1158/1535-7163.targ-21-p049","url":null,"abstract":"","PeriodicalId":20348,"journal":{"name":"Poster Presentations - Proffered Abstracts","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77441548","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}
S. Cohen-Gogo, Nisha Kanwar, Furqan Shaikh, R. Baertschiger, A. Shlien, D. Malkin, J. Putra, Ailish C. Coblentz, A. Villani, Abha A. Gupta, D. Morgenstern
{"title":"Abstract P136: Response to alpelisib in an adolescent with PIK3CA-mutated metastatic gastrointestinal stromal tumour","authors":"S. Cohen-Gogo, Nisha Kanwar, Furqan Shaikh, R. Baertschiger, A. Shlien, D. Malkin, J. Putra, Ailish C. Coblentz, A. Villani, Abha A. Gupta, D. Morgenstern","doi":"10.1158/1535-7163.targ-21-p136","DOIUrl":"https://doi.org/10.1158/1535-7163.targ-21-p136","url":null,"abstract":"","PeriodicalId":20348,"journal":{"name":"Poster Presentations - Proffered Abstracts","volume":"102 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74026246","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}