tbuckley/cabot-search huggingface dataset:
Abstract C091: Harnessing proteostatic vulnerabilities in pancreatic cancer
Authors: Sandra Vogt, Dafna Bar-Sagi
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) harbors mutations in KRAS in greater than 90% of cases and is characterized by a dense, fibrotic stroma that fosters the formation of a hypoxic, nutrient-poor tumor microenvironment, rendering tumor cells susceptible to proteotoxic stress. In order to prevent endoplasmic reticulum (ER) stress-induced cell death caused by accumulation of toxic protein aggregates, tumor cells must adapt proteostatic mechanisms including activation of the unfolded protein response (UPR) pathway and degradation of misfolded or aggregated proteins through proteasome-dependent or -independent mechanisms, such as ER-specific autophagy (ERphagy). Despite evidence suggesting that tumor cells may experience proteotoxic stress, little is known about the mechanisms pancreatic cancer cells employ to maintain proteostasis. We found that pancreatic cancer cells exhibit KRas-dependent constitutive UPR activation at the expense of ERphagy, suggesting that tumor cells preferentially employ UPR signaling to maintain proteostasis. Accordingly, mutant KRas pancreatic cancer cells have little to no aggregated proteins at baseline as a consequence of UPR activation. Furthermore, upon pharmacological enhancement of ER stress by 26S proteasome inhibition with bortezomib, ERphagy is engaged as a protective mechanism against UPR hyperactivation and apoptosis. In order to target protective ERphagy to promote apoptosis, we suppressed ERphagy activation through siRNA-mediated knockdown of ERphagy receptors under conditions of bortezomib-induced ER stress and found that depletion of CCPG1 but not other ERphagy receptors augmented the growth-suppressive effects of bortezomib due to greater UPR activation and accumulation of aggregated proteins. Overall, our findings implicate context-dependent reliance on both UPR signaling and ERphagy in pancreatic cancer cell survival and identify a targetable cell-intrinsic vulnerability that can leveraged for enhancing the cytotoxic effects of bortezomib, which alone is clinically ineffective in treating PDAC. Citation Format: Sandra Vogt, Dafna Bar-Sagi. Harnessing proteostatic vulnerabilities in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C091.
Abstract A044: Tumor-infiltrating lymphocyte density correlates with survival in pancreatic adenosquamous carcinoma
Authors: Saurav D. Haldar, Christopher D. Jakubowski, Su Jin Lim, Hao Wang, Richard A. Burkhart, Kelly Lafaro, William R. Burns, Jin He, Daniel A. Laheru, Elizabeth D. Thompson, Nilofer S. Azad
Journal: Cancer Research (2024)

Abstract Background: Pancreatic adenosquamous carcinoma (PASC) is a rare and aggressive form of pancreatic cancer, representing only 1-5% of cases. Histologically, it is defined by the presence of at least 30% squamous differentiation mixed with ductal adenocarcinoma. No standard therapies or prognostic biomarkers have been validated to date in this understudied disease. Methods: All patients diagnosed with pancreatic cancer in the Johns Hopkins Cancer Registry from 2013 to 2018 were queried for adenosquamous histology. Archived slides of available tumor specimens were examined to quantify the percentage of squamous differentiation and tumor-infiltrating lymphocyte (TIL) density. Descriptive statistics were used to summarize clinical, pathologic, and molecular characteristics. Kaplan-Meier estimates and log-rank tests were used for survival analyses. Results: Among a total of 8,908 patients queried, 155 patients with adenosquamous histology were identified. Median overall survival (OS) was 14.2 months and 7.5 months for resectable and unresectable/metastatic disease, respectively. Molecular tumor testing revealed frequent somatic mutations in KRAS, TP53, and SMAD4 in addition to multiple DNA damage repair genes. The percentage of squamous differentiation and TIL density was correlated with survival outcomes in a subset of 28 patients with evaluable tumor specimens. No association between the percentage of squamous differentiation and OS was identified. Of note, compared to those with low TIL density (0-10%), patients with an intermediate/high TIL density (&amp;gt;10%) exhibited significantly improved survival (median OS 36.3 vs 14.2 months, p = 0.011). Conclusions: For the first time, intermediate/high TIL density is associated with prolonged OS in a single-institution cohort of PASC patients. Prospective validation in larger cohorts is needed to establish prognostic biomarkers that can guide therapeutic decision-making in this lethal and under-examined disease subtype. Citation Format: Saurav D. Haldar, Christopher D. Jakubowski, Su Jin Lim, Hao Wang, Richard A. Burkhart, Kelly Lafaro, William R. Burns III, Jin He, Daniel A. Laheru, Elizabeth D. Thompson, Nilofer S. Azad. Tumor-infiltrating lymphocyte density correlates with survival in pancreatic adenosquamous carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A044.
Abstract A093: Deciphering acquired resistance to KRASG12D inhibition in a mouse model of pancreatic ductal adenocarcinoma
Authors: Julien Dilly, Laleh Abbassi, Connor J. Hennessey, Giselle A. Uribe, Brendan Parent, Annan Yang, Kevin S. Kapner, Ziyue Li, Shatavisha Dasgupta, Alexander Jordan, Megan T. Hoffman, Li Qiang, Felix P. Hambitzer, Seema Chugh, Alex K. Shalek, Stephanie K. Dougan, Brian M. Wolpin, Jonathan A. Nowak, Srivatsan Raghavan, Peter S. Winter, Andrew J. Aguirre
Journal: Cancer Research (2024)

Abstract KRAS is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC) and is mutationally activated in approximately 90% of cases, with the glycine-to-aspartic acid substitution at position 12 (p.G12D) being the most prevalent alteration. Mutations in this oncogene have been associated with more aggressive disease and poorer outcomes and have remained “undruggable” for more than three decades. However, the recent development of mutant-specific small molecule inhibitors of KRAS has given hope for the treatment of this highly lethal and treatment-refractory malignancy. Here we evaluated the genomic and transcriptional mechanisms of resistance to MRTX1133, a first-in-class inhibitor of KRASG12D, in an autochthonous mouse model of PDAC. We leveraged single-nucleus RNA sequencing and whole-exome sequencing on 16 samples from KPC mouse specimens (LSL-KrasG12D/+; LSL-Trp53R172H/+; p48-Cre) that were treated with either MRTX1133 or the vehicle, including 6 samples from mice that developed resistance to KRASG12D inhibition. Our analysis has uncovered that resistance is multifaceted and characterized by both emergent genomic and transcriptional features. Genetically, resistant tumors harbored clonal and subclonal amplifications in the HIPPO pathway, cell cycle regulators, and ABC transporters. Transcriptionally, we employed non-negative matrix factorization and identified recurrent gene expression programs in resistant and vehicle samples. Using this approach, we uncovered the existence of an intermediate phenotype between classical and mesenchymal cell states that is enriched in tumors with evolved resistance to MRTX1133. In summary, our study provides a high resolution genomic and transcriptional landscape of resistance to KRAS targeting in a preclinical in vivo model of PDAC, highlighting the complexity of treatment resistance and identifying various pathways and effectors that may serve as potential new targets for combination therapy. Citation Format: Julien Dilly, Laleh Abbassi, Connor J. Hennessey, Giselle A. Uribe, Brendan Parent, Annan Yang, Kevin S. Kapner, Ziyue Li, Shatavisha Dasgupta, Alexander Jordan, Megan T. Hoffman, Li Qiang, Felix P. Hambitzer, Seema Chugh, Alex K. Shalek, Stephanie K. Dougan, Brian M. Wolpin, Jonathan A. Nowak, Srivatsan Raghavan, Peter S. Winter, Andrew J. Aguirre. Deciphering acquired resistance to KRASG12D inhibition in a mouse model of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A093.
Abstract C059: Hub gene analysis identifies CAD as a potential mediator for drug resistance in pancreatic cancer
Authors: Foram Vyas, Barbara Grünwald, Kazeera Aliar, Gun Ho Jang, Grainne O'Kane, Thomas Kislinger, Steven Gallinger, Benjamin Haibe-Kains, Rama Khokha
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a complex disease pathobiology and poor treatment options, emphasizing the need for novel therapeutic targets. Hub genes have high connectivity (i.e., exceptionally many interaction partners), for example, certain proteases with numerous interaction partners. Thereby, hub genes are often central biological regulators and dysregulated proteolysis is indeed a key trait of malignant tissues. Here, we aimed to identify novel protease-related hub genes with potential involvement in pancreatic cancer. We applied an integrative computational approach to compartment-specific multiOMIC profiles of laser-capture micro-dissected human PDAC tissues (n = 32) and queried associations of identified candidate genes with clinical outcomes in early (n = 186) and advanced PDAC patients (n = 253). This identified 20 protease-related genes with ≥ 10 physically verified interaction partners in pancreatic cancer. Among these, the pyrimidine biosynthesis regulator gene CAD emerged as a potentially druggable target in pancreatic cancer. CAD expression was nearly restricted to the malignant PDAC epithelium. Furthermore, higher CAD expression was associated with significantly worse overall survival in patients with advanced but not resectable disease, suggesting a role in treatment response rather than disease progression. Moreover, patients with higher CAD expression specifically demonstrated poor response to mFFX but not Gemcitabine-nab-Paclitaxel treatment, which is in line with previous reports on CAD expression being protective against 5-Fluouracil, a component of FFX. Moving forward, we will interrogate the role of CAD in PDAC tissue biology and scrutinize its involvement in FFX resistance, using patient-derived organoids. Citation Format: Foram Vyas, Barbara Grünwald, Kazeera Aliar, Gun Ho Jang, Grainne O'Kane, Thomas Kislinger, Steven Gallinger, Benjamin Haibe-Kains, Rama Khokha. Hub gene analysis identifies CAD as a potential mediator for drug resistance in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C059.
Abstract A058: Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis
Authors: Ziheng Chen, I-Lin Ho, Giulio Draetta, Haoqiang Ying
Journal: Cancer Research (2024)

Abstract Mitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The essential contributions of mitochondrial metabolism to fuel tumor growth and resistance to therapy are now evident in multiple contexts. However, targeting of mitochondrial metabolism in the clinical setting has repeatedly failed, owing to a narrow therapeutic window and the remarkable ability of tumor cells to activate compensatory metabolic programs. Thus, it is essential to uncover additional mechanisms that may render cancer cells selectively susceptible to treatment and those that enable them to survive when exposed to mitochondrial metabolism-targeted drugs. Here, using pancreatic ductal adenocarcinoma (PDAC) as a disease model, we report that cellular and, in particular, mitochondrial lipid composition affects the sensitivity of cancer cells to pharmacological inhibition of electron transport chain complex I. Metabolomic, including lipidomic, analyses of patient-derived PDAC models uncovered a critical role for monosaturated fatty acids (MUFAs) and demonstrated that MUFA-linked ether phospholipids have a critical role to sustain homeostasis of mitochondrial reactive oxygen species (ROS). Blocking de novo ether phospholipid biosynthesis in the peroxisomes, sensitized PDAC cells to mitochondrial complex I inhibition by inducing mitochondrial ROS and lipid peroxidation. Biochemical analysis revealed a role of ether phospholipids in the assembly of mitochondrial supercomplexes and ROS production. Together, our data identify an ether phospholipid-dependent mechanism that regulates mitochondrial redox control and contributes to the sensitivity of PDAC cells to complex I inhibition. These findings might lead to novel approaches to target mitochondrial metabolism in cancer cells. Citation Format: Ziheng Chen, I-Lin Ho, Giulio Draetta, Haoqiang Ying. Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A058.
Abstract A095: ZNF274 suppresses the mesenchymal state, thereby causing intrinsic resistance to CDK7 inhibition
Authors: Jessica Gianopulos, Adrianne Wallace-Povirk, Sita Kugel
Journal: Cancer Research (2024)

Abstract Pancreatic Ductal Adenocarcinoma (PDA) can be characterized by two distinct transcriptional subtypes: classical and basal. The basal PDA subtype is more aggressive and has the worst overall survival. We have previously shown that the histone deacetylase (HDAC) Sirtuin 6 (SIRT6), a marker of the classical PDA subtype, can control sensitivity to CDK7 inhibitors. Interestingly, SIRT6 is part of the KAP1 repressive complex where it functions as an HDAC. This complex functions to maintain heterochromatin at specific regions of the genome by removing marks of open chromatin and installing marks of repressive chromatin with histone methyltransferases (HMT) and DNA methyltransferases (DNMT). The complex relies on a KRAB-Zinc Finger protein to bind DNA directly and modify chromatin at those regions. Since we found that SIRT6 can control sensitivity to CDK7 inhibition, we hypothesized that the KAP1 repressive complex is crucial for maintaining subtype-specific chromatin states and that manipulation of any part of this complex could alter subtype, thereby changing sensitivity to CDK7 inhibition. In a survey of basal and classical PDA cell lines, we found that the KRAB-Zinc Finger ZNF274 showed substantial differential expression, similar to SIRT6, and correlated with overall patient survival. We validated ZNF274 expression in PDA cell lines and organoids by western blot and immunofluorescence and found that classical PDA expressed high levels of ZNF274. Next, we investigated how loss of ZNF274 would affect classical PDA cells and found that knockdown of this protein induced an epithelial-to-mesenchymal (EMT) transition through increased ZEB1 expression. We analyzed protein and RNA expression of more EMT regulators and identified morphological changes representative of EMT. Therefore, this induction of EMT upon loss of ZNF274 could be initiating a subtype switch from classical PDA to basal. To determine if loss of ZNF274 and induction of the mesenchymal state could sensitize cells to CDK7 inhibition as we have previously shown, we performed ZNF274 knockdown in classical PDA and saw a dramatic increase in sensitivity to CDK7 inhibitors. Therefore, we have shown the KAP1 repressive complex to be important in regulating cell state and sensitivity of classical PDA to CDK7 inhibitors which we hope to exploit to improve patient responses to CDK7 inhibition therapy. Citation Format: Jessica Gianopulos, Adrianne Wallace-Povirk, Sita Kugel. ZNF274 suppresses the mesenchymal state, thereby causing intrinsic resistance to CDK7 inhibition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A095.
Abstract A059: Targeting pancreatic cancer metabolic dependencies through glutamine antagonism
Authors: Joel Encarnacion-Rosado, Alec C. Kimmelman, Robert Wild
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer. A factor that contributes to the poor prognosis of the disease is the complex tumor microenvironment (TME). The PDAC TME is composed of excessive fibrosis and desmoplasia, which creates a harsh environment resulting in hypoxia and altered nutrient availability. To promote survival and proliferation in this environment, PDAC cells can reprogram glutamine (Gln) metabolism. Previous studies have demonstrated that PDAC cells use Gln to support proliferation and redox balance. However, earlier attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and therapeutic resistance. We hypothesized that a Gln analogue, such as 6-Diazo-5-oxo-L-norleucine (DON), could broadly target Gln metabolism in PDAC and prevent rapid adaptation. Indeed, DON treatment led to a significant decrease in PDAC proliferation and a profound reduction of various metabolites involved in central carbon and nucleotide metabolism, suggesting that DON creates a metabolic crisis. In addition, we observed a significant decrease in tumor growth in various in vivo models (syngeneic, immunodeficient and PDXs) using DRP-104 (sirpiglenastat), a novel pro-drug version of DON that was designed to circumvent DON associated GI toxicity and allow the therapeutic exploration of broad Gln antagonism. Mechanistically, we found that ERK signaling is increased as a compensatory mechanism through the increased activity of receptor tyrosine kinases (RTKs). Combinatorial treatment of DRP-104 and Trametinib (MEK1/2) inhibitor led to a significant increase in survival in a syngeneic model PDAC. Taken together, these pre-clinical results suggest that broadly targeting Gln metabolism could provide a new therapeutic avenue for PDAC and that the combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome. Citation Format: Joel Encarnacion-Rosado, Alec C. Kimmelman, Robert Wild. Targeting pancreatic cancer metabolic dependencies through glutamine antagonism [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A059.
Abstract B092: CDK8 and CXCL2 remodel the tumor microenvironment to contribute to KRASG12D small molecule inhibition resistance in pancreatic ductal adenocarcinoma
Authors: Kathleen M. McAndrews, Krishnan K. Mahadevan, Bingrui Li, Amari M. Sockwell, Sami J. Morse, Patience J. Kelly, Michelle L. Kirtley, Meagan R. Conner, Sarah I. Patel, Shreyasee V. Khumbar, Kent A. Arian, Yasaman Barekatain, Barbara A. Moreno Diaz, Hengyu Lyu, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Navid Sobhani, Francesca Paradiso, Vincent Bernard, Paola Guerrero, Haoqiang Ying, Anirban Maitra, Timothy P. Heffernan, Raghu Kalluri
Journal: Cancer Research (2024)

Abstract Mutations in KRAS are a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with over 50% of PDAC patients presenting with KRASG12D mutations. The recent development of small molecule inhibitors targeting KRASG12D has enabled effective targeting of mutant KRAS signaling and suppression of tumor growth; however, the contribution of the tumor microenvironment to the therapeutic efficacy of KRASG12D inhibition and mechanisms of resistance to KRASG12D suppression remain to be fully elucidated. Here, we employed spatial transcriptomics and proteomics to evaluate cancer cell intrinsic and extrinsic responses to KRASG12D inhibition with MRTX1133. MRTX1133 treatment was associated with increased antigen presenting cells (APCs), T cells, and putative tumor-restraining fibroblasts within proximity to cancer cells, suggesting that antigen presentation and remodeling of the local microenvironment facilitates an effective response to KRASG12D inhibition. In the context of relapsed MRTX1133 treated tumors, single cell RNA sequencing and validation identified CDK8 as an intrinsic mediator of resistance and CXCL2 as an extrinsic mediator of resistance. Together, these studies identify APCs and CDK8 as therapeutic targets for enabling long term responses to small molecule KRASG12D inhibition with MRTX1133. Citation Format: Kathleen M. McAndrews, Krishnan K. Mahadevan, Bingrui Li, Amari M. Sockwell, Sami J. Morse, Patience J. Kelly, Michelle L. Kirtley, Meagan R. Conner, Sarah I. Patel, Shreyasee V. Khumbar, Kent A. Arian, Yasaman Barekatain, Barbara A. Moreno Diaz, Hengyu Lyu, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Navid Sobhani, Francesca Paradiso, Vincent Bernard, Paola Guerrero, Haoqiang Ying, Anirban Maitra, Timothy P. Heffernan, Raghu Kalluri. CDK8 and CXCL2 remodel the tumor microenvironment to contribute to KRASG12D small molecule inhibition resistance in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B092.