bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B04: High-level expression of oncogenic KRAS is required to transform LKB1 mutant tissue in vivo
Authors: Rackley Briana B. , Seong Chang-Soo , Gilbert-Ross Melissa 
Published: June 2021

Abstract
Although activating mutations in the GTPase KRAS are oncogenic and implicated in various malignancies, mutations in KRAS alone are inefficient to transform epithelia. In lung adenocarcinoma, KRAS mutations occur at high frequency and co-segregate with loss of the LKB1 tumor suppressor, a master serine/threonine kinase that phosphorylates and activates multiple AMPK family kinases to control energy homeostasis, cell polarity, and cell:matrix signaling. Despite our current knowledge of LKB1 biology, the complexity of the signaling pathway has precluded investigations into the precise mechanism by which alteration of this kinase contributes to oncogenic transformation and tumor progression in vivo. In the present study, we introduced mutations in Kras and Lkb1 in the genetically tractable organism Drosophila melanogaster. We show that low-level expression of oncogenic Kras (KrasLow) promotes the survival of Lkb1-mutant tissue, eventually leading to a G1 arrest, and concomitant overgrowth of the surrounding tumor microenvironment. Alternatively, high-level expression of oncogenic Kras (KrasHigh) promotes the neoplastic transformation of Lkb1-mutant tissue, leading to autonomous growth and increased cell cycle progression, invasion of mutant tissue into the brain, and the survival and growth of explanted tumor tissue in a wild-type Drosophila host. Interestingly, phosphorylation of the canonical Lkb1 target AMPK is maintained in KrasHigh/Lkb1 neoplastic tissue, but not in KrasLow/Lkb1 tissue. Finally, we analyzed TCGA Pan Lung Cancer data and show that high-level, but not low-level, expression of oncogenic KRAS results in worse overall survival in the context of LKB1 loss. Taken together, these data suggest that increasing levels of oncogenic KRAS, perhaps through mutant KRAS copy gains, are a driving event in the malignant transformation of LKB1-mutant tissue, and that the rewired AMPK signaling axis may offer a potential therapeutic target for patients with this subset of mutations.
Citation Format: Briana B. Rackley, Chang-Soo Seong, Melissa Gilbert-Ross. High-level expression of oncogenic KRAS is required to transform LKB1 mutant tissue in vivo [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B04.
Abstract B12: DOCK1 as a novel target for controlling RAS-driven cancer cell survival and invasion
Authors: Uruno Takehito , Fukui Yoshinori 
Published: June 2021

Abstract
Oncogenic RAS contributes to malignant phenotypes of cancer cells by stimulating macropinocytosis-dependent nutrient uptake and promoting invasive migration. Because these cellular activities require remodeling of the actin cytoskeleton, which is regulated by the Rho family GTPase Rac, we hypothesized that molecules involved in Rac activation downstream of oncogenic RAS may be valuable targets for cancer therapy. DOCK1 is a Rac-specific guanine nucleotide exchange factor (GEF) implicated in malignancy of breast cancers and glioma. We show that genetic inactivation of endogenous DOCK1 in various RAS-transformed cells markedly suppressed their matrix invasion, macropinocytosis, and survival under glutamine-deprived conditions. We developed a selective inhibitor of DOCK1 that binds to the catalytic domain of DOCK1 and blocks its GEF activity. This inhibitor 1-(2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-pyrrolidinylsulfonyl-2(1H)-pyridone (TBOPP) blocked DOCK1-mediated invasion and macropinocytosis without impairing the immune-regulatory functions of its closely related protein DOCK2. Furthermore, TBOPP treatment suppressed cancer metastasis and growth in vivo in mice. To further assess the role of DOCK1 in RAS-driven cancers, we established the KPC mouse pancreatic ductal adenocarcinoma model bearing DOCK1 conditional knockout allele. Our results demonstrate that targeting DOCK1 could be an effective approach to treat RAS-driven cancers.
Citation Format: Takehito Uruno, Yoshinori Fukui. DOCK1 as a novel target for controlling RAS-driven cancer cell survival and invasion [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B12.
Abstract B15: Dabrafenib-trametinib-induced pyrexia successfully treated with colchicine
Authors: Vera Jesus , Paludo Jonas , Kottschade Lisa , Block Matthew , Yan Yiyi , Loprinzi Charles , Markovic Svetomir 
Published: June 2021

Abstract
The most common adverse event (AE) of dabrafenib and trametinib (DT) is pyrexia, which has been reported to occur in up to 71% of patients. Pyrexia resulted in therapy discontinuation in up to 26% of patients who otherwise were benefiting from the treatment. Little is known about the pathogenesis and optimal management of this common AE. We hypothesized that the etiology of pyrexia in patients treated with DT could be extrapolated from DT-related cutaneous adverse effects in which a paradoxical MAPK pathway activation has been identified. We hypothesized that the mechanism of MAPK pathway activation with DT therapy is similar to that reported in patients with familial Mediterranean fever (FMF), a rare, inherited condition characterized by episodes of fever and rash that responds exceedingly well to colchicine-based therapy. Based on this association, our group explored the use of oral colchicine for the treatment of DT-associated pyrexia in five patients with metastatic melanoma.
Citation Format: Jesus Vera, Jonas Paludo, Lisa Kottschade, Matthew Block, Yiyi Yan, Charles Loprinzi, Svetomir Markovic. Dabrafenib-trametinib-induced pyrexia successfully treated with colchicine [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B15.
Abstract B33: Inhibition of Ras using Affimers
Authors: Rao Ajinkya , Haza Kataryzna , Trinh Chi , Edwards Thomas , Tomlinson Darren 
Published: June 2021

Abstract
Ras proteins function as binary switches in order to mediate a wide range of signaling events and are one of the most frequently mutated oncoproteins in human cancers. However, progress in targeting Ras has been slow owing to the lack of obvious druggable sites. Recently, numerous binding proteins have been developed that probe Ras function, which have identified some allosteric sites and have opened new avenues for drug discovery. Affimers are now an established class of binding proteins. They consist of two variable regions that confer molecular recognition with target proteins and molecules. We have isolated Affimers against KRas using phage display. From the phage screen, seven unique binders were isolated and tested in SOScat catalyzed nucleotide exchange reaction to identify inhibitors of nucleotide exchange. Three Affimers, K3, K6 and K37, were the most potent inhibitors of this reaction, with K3 also inhibiting Ras interaction with the Ras binding domain of Raf. To understand the molecular mechanisms of inhibiting both nucleotide exchange and interaction with Raf, the X-ray crystal structure of Affimer K3-KRas complex was solved to 2.1 Å resolution. The Affimer interacts with Switch II region of KRas, causing the α-2 helix region to shift outwards to reveal a hydrophobic pocket that has not been targeted by any other non-antibody binding proteins. It is speculated that the shift in the switch II domain will cause a steric clash with the Ras binding domain of Raf. These results show that Affimers can select for protein conformations not previously identified by other reagents and may aid in further developing Ras binding compounds.
Citation Format: Ajinkya Rao, Kataryzna Haza, Chi Trinh, Thomas Edwards, Darren Tomlinson. Inhibition of Ras using Affimers [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B33.
Abstract B44: KRAS and RAS signaling network is co-regulated and can be therapeutically blocked by targeting eIF4A dependent translation program
Authors: Singh Kamini , Lin Jianan , Lecomte Nicolas , Mohan Prathibha , Gokce Askan , Sanghvi Viraj , Olivera Grbovic-Huezo , Jiang Man , Burčul Antonija , Stark Stefan , Viale Agnes , Romesser Paul B. , Destanchia Elisa , Bagni Rachel , Rätsch Gunnar , Leach Steve D. , Ouyang Zhengqing , Wendel Hans-Guido 
Published: June 2021

Abstract
New and effective therapeutics are urgently needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). The eIF4A/DDX2 RNA helicase drives translation of mRNAs with highly structured 5′UTRs. The natural compound silvestrol and synthetic analogues are potent and selective inhibitors of eIF4A1/2 that show promising activity in models of hematologic malignancies. Here, we show silvestrol analogues have nanomolar activity against PDAC cell lines and organoids in vitro. Moreover, we see single-agent activity in the KRAS/p53 mouse PDAC model and also against PDAC xenograft and primary, patient-derived PDAC tumors. These therapeutic effects occur at nontoxic dose levels. Transcriptome-wide ribosome profiling, analyses of protein and gene expression, and translation reporter studies reveal that KRAS and the RAS signaling network is co-regulated by translation in an eIF4A dependent manner. eIF4A inhibitors block an oncogenic translation program in PDAC cells that includes G-quadruplex containing mRNAs such as KRAS, MYC, YAP1, MET, SMAD3, TGFβ and other components of the RAS signaling network. Together, our data indicate that pharmacologic inhibition of eIF4A disrupts oncoproteins production and shows efficacy across several PDAC models.
Citation Format: Kamini Singh, Jianan Lin, Nicolas Lecomte, Prathibha Mohan, Askan Gokce, Viraj Sanghvi, Grbovic-Huezo Olivera, Man Jiang, Antonija Burčul, Stefan Stark, Agnes Viale, Paul B. Romesser, Elisa Destanchia, Rachel Bagni, Gunnar Rätsch, Steve D. Leach, Zhengqing Ouyang, Hans-Guido Wendel. KRAS and RAS signaling network is co-regulated and can be therapeutically blocked by targeting eIF4A dependent translation program [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B44.
Abstract IA03: KRAS Q61H preferentially signals through the MAPK pathway in non-small cell lung cancer
Authors: Zhou Zhiwei , Ambrogio Chiara , Bera Asim , Qing Li , Cheng-Xiong Xu , Janne Pasi , Westover Ken 
Published: June 2021

Abstract
RAS proteins are guanosine triphosphatases (GTPases) that function as binary switches cycling between inactive (GDP-bound) and active (GTP-bound) states. Activated RAS proteins bind RAS effectors including RAF kinases, PI3K, RalGDS, and others. Conversion from GDP to GTP is stimulated by guanine nucleotide exchange factors (GEFs) while conversion to the inactive GDP-bound form is mediated by GTPase activating proteins (GAPs). Mutations can alter the signaling properties of RAS proteins through a number of means including modification of the GTPase activity, nucleotide exchange rate, or effector binding characteristics. Understanding these differences may enable new therapeutic approaches to specific RAS mutations associated with human disease. We will discuss how codon 61 mutations in KRAS can result in profoundly reduced intrinsic and GAP-stimulated GTPase activity, and a relatively high affinity for RAF-RBD compared to other oncogenic KRAS mutations, and how these features may enable therapeutic options for cancers bearing RAS mutations at codon 61.
Citation Format: Zhiwei Zhou, Chiara Ambrogio, Asim Bera, Li Qing, Xu Cheng-Xiong, Pasi Janne, Ken Westover. KRAS Q61H preferentially signals through the MAPK pathway in non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA03.
Abstract IA06: Oncogenic Ras control of the tumor immune microenvironment
Authors: Downward Julian 
Published: June 2021

Abstract
Despite RAS proteins being exceptionally well-validated cancer targets, little progress has been made towards targeting them effectively in the clinic. We have optimized combination targeting of effector pathways downstream of RAS for specific activity on KRAS mutant cells, with combinations targeting MEK, IGF-1R and mTORC1 being highly effective in preclinical models. Replacing MEK with G12C KRAS inhibitor reduces the toxicity of the combination. However, these combinations are not able to eradicate tumors, which recur once treatment is stopped. In order to improve the effectiveness of RAS-targeted therapies, we have investigated the mechanisms whereby RAS signaling pathways can promote local immune suppression in the tumor microenvironment through inducing the expression of immune checkpoint proteins, immune suppressive cytokines, and extracellular enzymes. One such pathway involves the control of mRNA stability of PD-L1 and multiple cytokines by the 3′AU rich element binding protein, tristetraprolin. Another pathway that appears to be strongly upregulated in RAS mutant tumors is signaling by extracellular adenosine, which is strongly immunosuppressive. In order to test potential combinations of targeted therapies and immunotherapies resulting from these studies, we have developed new mouse models for KRAS mutant lung cancer that show more realistic interaction of the immune system with the tumor, which is not seen in existing genetically engineered mouse models used to study RAS mutant cancer due their lack of tumor heterogeneity and mutational burden. This work also involves detailed analysis of the tumor immune microenvironment using imaging mass cytometry and comparison between manipulatable mouse models and human clinical samples from the TRACERx lung cancer study.
Citation Format: Julian Downward. Oncogenic Ras control of the tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA06.
Abstract IA23: Developing therapies for Ras-driven cancers
Authors: Cichowski Karen 
Published: June 2021

Abstract
While selective kinase inhibitors have changed the standard of care in cancers that are driven by oncogenic kinases, there are currently few treatment options for malignancies that lack a “targetable” oncogenic driver. Ras-driven cancers are particularly problematic: agents that target individual Ras effector pathways are largely ineffective and successful therapeutic combinations have not yet been identified. Therefore, it is imperative that we rationally conceptualize and test new therapeutic combinations that either 1) function to suppress orthogonal pathways in tumors, 2) converge on specific cancer cell vulnerabilities, and/or 3) exploit multiple therapeutic modalities. In this presentation various combinatorial strategies designed to inhibit Ras effector kinases and other targets will be discussed. By dissecting the mechanism by which promising combinations are working in preclinical models, we have uncovered nodal points of convergence between these distinct pathways and have identified new vulnerabilities that can be targeted in Ras-driven tumors.
Citation Format: Karen Cichowski. Developing therapies for Ras-driven cancers [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA23.
Abstract IA24: Oncogenic Ras-dependent tumor cell vulnerabilities
Authors: Bar-Sagi Dafna 
Published: June 2021

Abstract
A longstanding goal of the work in my lab has been to identify strategies by which the oncogenic potential of mutant Ras can be compromised. The overall framework for our efforts is based on the wealth of evidence indicating that the robustness of the transformed phenotype that is displayed by cells that harbor oncogenic Ras reflects the engagement of a unique set of biologic processes that are critical for tumor initiation and progression. Because by definition these processes represent tumor cell-specific vulnerabilities, our working premise has been that knowledge of the mechanisms downstream of oncogenic Ras that control these processes could be leveraged to develop tumor-specific targeting modalities. We have been testing this premise in the context of Ras-dependent processes that control metabolic adaptation, immune evasion, stress resistance, and proliferative capacity. Recent observations and lessons learned will be discussed.
Citation Format: Dafna Bar-Sagi. Oncogenic Ras-dependent tumor cell vulnerabilities [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA24.
Abstract IA32: Interplay between RAF inhibitors and RAS
Authors: Zhang Ying , Bollag Gideon 
Published: June 2021

Abstract
Ever since RAF was shown to be a key downstream effector of RAS in the early 90s, RAF inhibition has been a goal within the drug discovery community. Sorafenib, an early entrant to the RAF armamentarium, was discovered through biochemical RAF inhibition assays with the goal of disrupting RAS signaling. Anticancer efficacy that was demonstrated through clinical trials was likely through “off-target” inhibition of VEGF receptors, and RAF is not effectively inhibited in RAS-mutant tumor cells. Furthermore, BRAF-mutant tumors were also poorly targeted by sorafenib, most likely because the “type 2” binding mode is ineffective against the activated BRAF kinase. Subsequently, compounds such as vemurafenib, dabrafenib, and encorafenib were developed as “type 1” inhibitors that target the active form of BRAF kinase: these inhibitors show efficacy in many BRAF-mutant tumors. Curiously, these RAF inhibitors cause certain side effects that have been attributed to the “RAF inhibitor paradox”: the ERK pathway is paradoxically stimulated by RAF inhibitors in cells with an activated RAS pathway. To overcome this liability, the next generation of RAF inhibitors dubbed “paradox breakers” were developed. As a BRAF-specific dimer disruptor, PLX8394 selectively inhibits ERK signaling in tumors bearing both monomer- and dimer-dependent BRAF mutants, including BRAF fusions and splice variants, while sparing RAF function in normal cells and avoiding paradoxical ERK activation in RAS-mutant cells. A converse effort seeks to take advantage of the paradox to identify RAS cell liabilities. By hyperstimulating the ERK pathway, “paradox activators” could tip the balance in favor of cellular disharmony. Future efforts exploiting this mechanism will enhance the context for thinking about RAF and near-neighbor targets in RAS tumors and guide the judicious selection of combination therapies involving RAF-targeting agents and other therapeutics.
Citation Format: Ying Zhang, Gideon Bollag. Interplay between RAF inhibitors and RAS [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA32.
Abstract PR06: Combinations with CDK4/6 inhibitors to treat cancers with mutations in both KRAS and CDKN2A
Authors: Litchfield Lacey , Kapoor Avnish , Wu Wenjuan , Gong Xueqian , Webster Yue , Peng Sheng-Bin , Bhagwat Shripad , Merzoug Farhana , Buchanan Sean G. 
Published: June 2021

Abstract
Oncogenic KRAS mutations commonly co-occur with loss of CDKN2A in pancreas and lung cancer. Both mutations are known to activate D-cyclin dependent kinases and therefore may confer sensitivity to drugs that inhibit CDK4 and CDK6 (CDK4/6i). Indeed, preclinical studies have shown that KRAS/CDKN2A double-mutant cancers are reasonably sensitive to CDK4/6 inhibitors and the CDK4/6i abemaciclib showed evidence of benefit in clinical studies of KRAS-mutant NSCLC (1) (http://www.ascopost.com/News/58135). However, despite the encouraging result, abemaciclib did not meet a prespecified overall survival endpoint in the JUNIPER trial, and it has been shown that failure to suppress CDK2 activity diminishes the antiproliferative activity of CDK4/6i in KRAS/CDKN2A mutant cancer cells (2). Since CDK2-specific inhibitors are not available for clinical combination strategies, it is unclear how to exploit this discovery. We employed CRISPR and shRNA genome-wide library screens to identify alternate mechanisms to potentiate the CDK4/6 inhibitor abemaciclib in this class of cancer. Depletion of Src family or Ras-MAPK pathway genes emerged as consistent hits in both lung and pancreas cancer cells with KRAS/CDKN2A mutations. Inhibitors of Src family or Ras-MAPK pathway kinases led to a strong suppression of CDK2 activity and apoptosis when combined with abemaciclib. Across a panel of cancer cell lines, ERKi LY3214996 combined with abemaciclib potently inhibited the growth of KRAS/CDKN2A mutant cancer cells. The combination of LY3214996 with abemaciclib was well tolerated in vivo and caused regressions in mice bearing human KRAS/CDKN2A mutant tumor xenografts, supporting the clinical examination of this drug combination.
References
1. Patnaik A et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov 2016;6:740-53.
2. Gong X et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK6 inhibitor abemaciclib. Cancer Cell 2017;32:761-76 e766.
This abstract is also being presented as Poster A33.
Citation Format: Lacey Litchfield, Avnish Kapoor, Wenjuan Wu, Xueqian Gong, Yue Webster, Sheng-Bin Peng, Shripad Bhagwat, Farhana Merzoug, Sean G. Buchanan. Combinations with CDK4/6 inhibitors to treat cancers with mutations in both KRAS and CDKN2A [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr PR06.