bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA12: Widespread rewiring of genetic interaction networks upon cancer pathway activation
Authors: Boutros Michael 
Published: December 2017

Abstract
Genetic interactions can reconstruct the wiring diagram of biological processes in health and disease. Gene-gene interactions are identified by simultaneously perturbing multiple gene products and identifying instances when the expected and experimentally measured phenotypes differ, e.g. aggravating or buffering phenotypic outcomes. Systematic gene-gene depletion experiment have been used to build comprehensive maps of cellular processes in unicellular and multicellular organisms, to place novel components into the context of known pathways and delineate epistatic relationships between components.
Cellular signaling networks coordinate physiological processes in all multicellular organisms. Within signaling networks, the interplay of different modules controls signaling activity dependent onto the cellular context. We here generated a context-dependent genetic interaction network of a Wnt signaling pathway, which has been implicated in many developmental and oncogenic processes. To assess changes in genetic network architecture, we measured &gt;290,000 double perturbations in a baseline state, after activation by Wnt ligands or loss of the tumor suppressor APC. We found that genetic interactions within the Wnt network globally rewired after pathway activation. Distinct groups of responsive functional relations were identified in the between-state or state-specific networks. State-dependent and between-state genetic interaction maps identified responsive functional modules in networks with specific functions.
Citation Format: Michael Boutros. Widespread rewiring of genetic interaction networks upon cancer pathway activation [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA12.
Abstract IA16: Systematic mapping and modeling of genetic interaction networks in cancer cells
Authors: Ideker Trey 
Published: December 2017

Abstract
We have developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbation coupled to robust analysis of growth kinetics. To demonstrate this approach, we targeted all gene pairs among a set of 73 known cancer genes with multiplexed guide RNAs in two cell lines, testing 23,652 combinations. Numerous therapeutically relevant interactions are identified, most private to one cell line. In parallel, we are developing bioinformatic approaches that analyze genetic interactions to construct hierarchical models of cancer pathways. I will discuss means by which these hierarchical models can be used to aggregate and interpret tumor mutations.
Citation Format: Trey Ideker. Systematic mapping and modeling of genetic interaction networks in cancer cells [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA16.
Abstract IA20: Chemical-genetic interaction maps for precision therapies in breast and ovarian cancers
Authors: Bandyopadhyay Sourav 
Published: December 2017

Abstract
There is an urgent need in oncology to link molecular aberrations in tumors with therapeutics that can be administered in a personalized fashion. One approach identifies synthetic-lethal genetic interactions or emergent dependencies that cancer cells acquire in the presence of specific mutations. Using breast epithelial cells as a base we have developed methodologies to connect tumor mutations with drug sensitivity using quantitative functional genomic screens to create chemical-genetic interaction maps. The focus of the lab is to use these maps to uncover new synthetic-lethal relationships and identify new biomarkers for targeted as well as chemotherapy. I will describe new approaches to use these quantitative maps to uncover drug mechanism of action as well as integrate with cancer cell line collections to predict drug responses in cancer.
Citation Format: Sourav Bandyopadhyay. Chemical-genetic interaction maps for precision therapies in breast and ovarian cancers [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA20.
Abstract IA21: Systematic, network-based elucidation of synthetic lethal proteins and synergistic compounds
Authors: Califano Andrea 
Published: December 2017

Abstract
Given the complex nature of cancer and the cell's ability to effectively compensate for individual perturbation through evolutionarily honed adaptive mechanisms, there is strong expectation that combination therapy approaches may be required to address the limitations that have emerged from single agent therapy. Synthetic lethality provides strong biological rationale supporting this observation, although mechanisms of compound synergy and sensitization are in general more complex than individual gene-pair interactions. Synthetic lethal genes have been elucidated mainly via large-scale screens in model organisms, or by pooled shRNA/CRISPR screens in cells harboring specific genetic events, or based on mechanistic understanding of specific pathways. These methodologies are laborious, expensive, and prone to significant false positive and negative rates due to the nature of pooled screens. More importantly, results are often idiosyncratic, depending on the specific genetic and epigenetic context of the cellular models used in the analysis.
To address these challenges, we have developed network-based methods to identify master regulator proteins that are responsible for maintaining tumor state, despite being rarely mutated using only patient-derived data. Master regulators are highly enriched in synthetic lethal interactions that can be elucidated computationally, via protein-target analysis. Furthermore, the approach can be trivially extended to elucidate synergistic drug interaction, based on perturbational assays of individual compounds. In this presentation, we will address the discovery of synthetic lethal genes and synergistic compounds in several tumor contexts, including lymphoma, breast cancer, prostate cancer, and glioma, which has led to the design and implementation of novel clinical trials. We will also discuss integration of these methodologies into an N of 1 protocol, which is currently enrolling 260 patients across 14 distinct malignancies.
Citation Format: Andrea Califano. Systematic, network-based elucidation of synthetic lethal proteins and synergistic compounds [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA21.
Abstract IA22: Exploiting the heterogeneity of mutant Kras lung tumors to improve therapy
Authors: Martins Carla 
Published: December 2017

Abstract
Lung cancer is currently the most lethal cancer worldwide with non-small cell lung carcinoma (NSCLC) accounting for ~85% of all cases. The vast majority of lung cancer patients present with locally advanced, inoperable or metastatic disease and median survival at this stage remains low. Targeted therapies are already improving treatment outcomes, but frequent mutations such as those affecting KRAS (present in ~30% of lung adenocarcinomas, a common subtype of NSCLC) still remain untargetable. Our lab aims to define new vulnerabilities associated with these aggressive and largely therapy-resistant tumors. To achieve this, we are characterizing the mechanisms that drive the malignant progression of mutant Kras lung tumors, using mouse models that closely recapitulate human lung adenocarcinoma. Using a multidisciplinary approach we recently identified distinct genetic, transcriptional and metabolic signatures between low grade and high grade mutant Kras lung tumors. In particular, we showed that high grade mutant Kras lung adenocarcinomas frequently exhibit extra copies of mutant Kras, implying that enhanced mutant Kras activity is positively selected during malignant progression. Moreover, we showed that the gain of just a single mutant copy (single vs double mutant) has a major effect on lung tumour cells in vitro and in vivo, leading to enhanced metastatic potential and metabolic rewiring. In turn, this metabolic rewiring creates unique dependences that can be exploited to selectively target advanced mutant Kras lung tumours. Our work shows that mutant Kras lung tumors are not a single disease, comprising two classes of tumors with mutant Kras allelic content-dependent prognosis and therapeutic susceptibilities. This intrinsic tumor heterogeneity is also present in the human disease and may have contributed to the poor therapeutic responses often associated with mutant KRAS lung tumors in humans. We are currently determining whether this metabolic heterogeneity can be exploited to improve the targeting of human mutant KRAS adenocarcinoma.
Citation Format: Carla Martins. Exploiting the heterogeneity of mutant Kras lung tumors to improve therapy [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA22.
Abstract IA23: Overcoming drug resistance and tumor heterogeneity in gastrointestinal cancers
Authors: Corcoran Ryan B. 
Published: December 2017

Abstract
Personalized cancer medicine approaches, inhibiting kinases in tumors driven by defined genomic alterations, have demonstrated striking efficacy in many cancer types. However, the development of drug resistance is a major limitation to the efficacy of targeted therapies in oncology. Identifying and understanding the molecular mechanisms driving resistance may foster opportunities to develop therapeutic strategies to overcome resistance. For example, in the ~10% of colorectal cancer patients whose tumors harbor BRAF V600 mutations, we have found that feedback reactivation of MAPK signaling, often mediated by EGFR, underlies the relative insensitivity of these cancers to RAF inhibitors. The development of targeted therapy combination strategies to block feedback reactivation of MAPK signaling has led to marked improvements in response rates for these patients from ~5% to &gt;30% over the past few years. However, in patients who respond to these targeted combinations, the rapid development of acquired resistance still limits clinical benefit. Acquired resistance in BRAF mutant colorectal cancer and in other molecularly-defined tumor types can be marked by the development of extensive molecular heterogeneity due to the selection of sub-clonal tumor cell populations, capable of growing under drug pressures, which poses significant diagnostic and therapeutic challenges. We will present data demonstrating how a single-lesion biopsy at disease progression to diagnose the mechanism of acquired resistance can vastly underrepresent the molecular heterogeneity of resistant tumor clones in an individual patient, and may fail to detect the existence of distinct but important resistance mechanisms that can drive mixed or lesion-specific responses and treatment failure to subsequent targeted therapy. By contrast, liquid biopsy approaches analyzing circulating tumor DNA have the potential to detect the presence of simultaneous resistance mechanisms residing in separate metastases in a single patient and to monitor the effects of subsequent therapies on specific sub-clonal tumor cell populations. These findings highlight the critical role of tumor heterogeneity in driving therapeutic resistance and how convergent targeted therapy strategies blocking common signaling nodes capable of overcoming multiple resistance mechanisms may be needed.
Citation Format: Ryan B. Corcoran. Overcoming drug resistance and tumor heterogeneity in gastrointestinal cancers [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA23.
Abstract PR01: A functional variomic chemi-genetic screen in C. elegans identifies new synthetic lethal interactions with PARP inhibition that are conserved from worm to human
Authors: O'Neil Nigel J. , Bailey Melanie L. , Hieter Philip 
Published: December 2017

Abstract
Poly ADP-ribose polymerase (PARP) inhibitors are anti-cancer therapeutics that are synthetic lethal (SL) with mutations affecting the homologous recombination genes BRCA1 or BRCA2. Previous work from our lab found that cohesin mutations, which are common in a range of tumour types, also confer sensitivity to PARP inhibition. We want to extend the SL profile of PARP inhibitors to identify the full spectrum of genetic variants that result in sensitivity to PARP inhibitors alone or in combination with DNA damaging agents.
To this end, we are using the model organism Caenorhabditis elegans to screen for new SL interactions with PARP inhibitors. C. elegans provides an excellent in vivo system with which to investigate SL interactions with cancer-associated mutations, as many of the pathways and genes implicated in cancer are conserved between humans and C. elegans. In many ways, C. elegans is an animal model that combines the technical advantages of a single celled organism, such as yeast, with increased developmental complexity and a gene complement more akin to humans.
We have developed a high throughput in vivo variomics approach using the C. elegans Million Mutation Project strain collection to screen 2,000 mutagenized and sequenced strains containing &gt;800,000 homozygous genetic variations. To date we have found 16 strains that were sensitive to the PARP inhibitor olaparib. Frequency analysis of the variants in the sensitive strains identified multiple mutations affecting mus-81 and eme-1, which comprise the structure specific Mus81 endonuclease. Further investigation of the interaction with the Mus81 endonuclease mutants found that PARP inhibitor-treated mus-81 and eme-1 mutants exhibit profound somatic proliferation defects characterized by persistent anaphase bridges and that the mus-81 PARP inhibitor-mediated synthetic lethality was not suppressed by loss of non-homologous end joining proteins.
We found that the synthetic lethality between MUS81 mutations and PARP inhibitor treatment is conserved in human cells. Similar to C. elegans, PARP inhibitor treated MUS81 knockout cells accumulate anaphase bridges and exhibit a phenotype distinct from PARP inhibitor treated BRCA2 knockout cells.
Our variomic screening approach has identified new SL interactions with PARP inhibitors and has expanded our understanding of the mechanism underlying PARP inhibitor-mediated synthetic lethality.
Citation Format: Nigel J. O’Neil, Melanie L. Bailey, Philip Hieter. A functional variomic chemi-genetic screen in C. elegans identifies new synthetic lethal interactions with PARP inhibition that are conserved from worm to human [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr PR01.
Abstract PR03: Linking AP/MS-driven protein-protein interaction networks and combination CRISPR/sgRNA screens defines new Kras effectors and target candidates for non-small cell lung cancer
Authors: Kelly Marcus R. , Kyuho Han , Jeng Edwin E. , Morgans David , Kostyrko Kaja , Simpson David , Gwinn Dana , Sweet-Cordero Alejandro , Bassik Michael C. , Jackson Peter K. 
Published: December 2017

Abstract
The Kras pathway is a central driver in prevalent and deadly cancers including pancreas, colon and lung. Despite decades of work studying the Raf and PI3 kinase pathways downstream of Kras, therapies targeted to these pathways have shown varied responses in tumors
To better understand whether important Kras dependences have been overlooked, we used tandem affinity purification of Kras, Hras, and Nras interactors and a set of baits representing ~50 interacting pathway regulators, and have compared these interactions in Kras transformed A549 NSCLC lines versus an isogenic shRNA Kras knockdown line, to identify key protein-protein interactions (PPIs) linked to Kras effector activity. These interactions were curated and compared to public PPI, genetic susceptibility, and other multiomics data to assemble a physical PPI map annotated with important functional determinants. This functional map was used to construct a library of 114 selected sgRNAs (10 guides per gene) and screened in a 1140 x 1140 dual sgRNA vector system to look for quantitative changes in single and dual genetic dependencies in A549 cell growth. We discovered a considerable number of new KRAS GTP-specific effectors important in NSCLC cancer, many with strong mutations patterns supported by TCGA data and validated by in vitro biochemical assay. We will present these data and additional validation studies on two pathways including the Radil-Rap1-Kif14 pathway for cell migration and an extensive interaction of the Kras pathway with Ral and Rap GTPase family guanine nucleotide exchange factors. These new effectors underscore limitations in our functional understanding of transformation in Kras-driven tumors and suggest specific new targets for these critical tumors.
Citation Format: Marcus R. Kelly, Han Kyuho, Edwin E. Jeng, David Morgans, Kaja Kostyrko, David Simpson, Dana Gwinn, Alejandro Sweet-Cordero, Michael C. Bassik, Peter K. Jackson. Linking AP/MS-driven protein-protein interaction networks and combination CRISPR/sgRNA screens defines new Kras effectors and target candidates for non-small cell lung cancer [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr PR03.
Abstract PR06: CRISPR screens identified drivers of endocrine resistance and synthetic lethal vulnerabilities in breast cancer
Authors: Xiao Tengfei , Li Wei , Wang Xiaoqing , Xu Han , Wu Qiu , Jiang Peng , Yang Jixin , Fei Teng , Zang Chongzhi , Liao Qi , Rennhack Jonathan , Andrechek Eran , Li Nanlin , Jeselsohn Rinath , Liu Shirley X. , Brown Myles 
Published: December 2017

Abstract
Estrogen receptor positive (ER+) breast cancer is treated with endocrine therapies, although in advanced disease therapeutic resistance almost invariably develops. Using genome-wide CRISPR screens we identified genes essential for the growth of ER+ breast cancers. More importantly, we also identified genes whose loss confers endocrine resistance. Notably the expression of c-src tyrosine kinase (CSK) is driven by estrogen yet loss of CSK promoted estrogen independent growth. A synthetic lethality screen for CSK loss identified the p21 protein-activated kinase (PAK2) which becomes activated by SRC-family kinases (SFK) in the absence of CSK. CSK loss or PAK2 over-expression predict worse clinical outcome in breast cancer cohorts. Inhibitors of PAK2 or SFK block estrogen-independent breast tumor growth. These findings reveal an estrogen-induced negative feedback loop that constrains the growth of ER+ tumors thereby limiting the efficacy of therapies that inhibit ER and suggest a previously unappreciated therapeutic route to overcoming endocrine resistance.
Citation Format: Tengfei Xiao, Wei Li, Xiaoqing Wang, Han Xu, Qiu Wu, Peng Jiang, Jixin Yang, Teng Fei, Chongzhi Zang, Qi Liao, Jonathan Rennhack, Eran Andrechek, Nanlin Li, Rinath Jeselsohn, Shirley X. Liu, Myles Brown. CRISPR screens identified drivers of endocrine resistance and synthetic lethal vulnerabilities in breast cancer [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr PR06.
Abstract 08: Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas
Authors: Lu Chao , Papillon-Cavanagh Simon , Gayden Tenzin , Mikael Leonie G. , Bechet Denise , Karamboulas Christina , Ailles Laurie , Karamchandani Jason , Marchione Dylan M. , Garcia Benjamin A. , Weinreb Ilan , Goldstein David , Lewis Peter W. , Dancu Octavia-Maria , Dhaliwal Sandeep , Stecho William , Howlett Christopher J. , Mymryk Joe S. , Barrett John W. , Nichols Anthony C. , Allis C David , Majewski Jacek , Jabado Nada 
Published: December 2017

Abstract
Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs) are deadly and common cancers. Recent genomic studies implicate multiple genetic pathways, including cell signaling, cell cycle and immune evasion, in their development. Here we analyze public data sets and uncover a previously unappreciated role of epigenome deregulation in the genesis of 13% of HPV-negative HNSCCs. Specifically, we identify novel recurrent mutations encoding p.Lys36Met (K36M) alterations in multiple H3 histone genes. We further validate the presence of these alterations in multiple independent HNSCC data sets and show that, along with previously described NSD1 mutations, they correspond to a specific DNA methylation cluster. The K36M substitution and NSD1 defects converge on altering methylation of histone H3 at K36 (H3K36), subsequently blocking cellular differentiation and promoting oncogenesis. Our data further indicate limited redundancy for NSD family members in HPV-negative HNSCCs and suggest a potential role for impaired H3K36 methylation in their development. Further investigation of drugs targeting chromatin regulators is warranted in HPV-negative HNSCCs driven by aberrant H3K36 methylation.
Citation Format: Chao Lu, Simon Papillon-Cavanagh, Tenzin Gayden, Leonie G. Mikael, Denise Bechet, Christina Karamboulas, Laurie Ailles, Jason Karamchandani, Dylan M. Marchione, Benjamin A. Garcia, Ilan Weinreb, David Goldstein, Peter W. Lewis, Octavia-Maria Dancu, Sandeep Dhaliwal, William Stecho, Christopher J. Howlett, Joe S. Mymryk, John W. Barrett, Anthony C. Nichols, C David Allis, Jacek Majewski, Nada Jabado. Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 08.