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Computer Science > Computation and Language

Title: realm: reference resolution as language modeling.

Abstract: Reference resolution is an important problem, one that is essential to understand and successfully handle context of different kinds. This context includes both previous turns and context that pertains to non-conversational entities, such as entities on the user's screen or those running in the background. While LLMs have been shown to be extremely powerful for a variety of tasks, their use in reference resolution, particularly for non-conversational entities, remains underutilized. This paper demonstrates how LLMs can be used to create an extremely effective system to resolve references of various types, by showing how reference resolution can be converted into a language modeling problem, despite involving forms of entities like those on screen that are not traditionally conducive to being reduced to a text-only modality. We demonstrate large improvements over an existing system with similar functionality across different types of references, with our smallest model obtaining absolute gains of over 5% for on-screen references. We also benchmark against GPT-3.5 and GPT-4, with our smallest model achieving performance comparable to that of GPT-4, and our larger models substantially outperforming it.

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• Published: 08 April 2024

Tumor-selective activity of RAS-GTP inhibition in pancreatic cancer

• Urszula N. Wasko 1 , 2   na1 ,
• Jingjing Jiang 3   na1 ,
• Tanner C. Dalton 1 , 2 ,
• Alvaro Curiel-Garcia   ORCID: orcid.org/0000-0001-6249-3267 1 , 2 ,
• A. Cole Edwards 4 ,
• Yingyun Wang 3 ,
• Bianca Lee 3 ,
• Margo Orlen   ORCID: orcid.org/0000-0002-9834-6282 5 ,
• Sha Tian 6 ,
• Clint A. Stalnecker   ORCID: orcid.org/0000-0002-0570-4416 7 , 8 ,
• Kristina Drizyte-Miller 7 ,
• Marie Menard 3 ,
• Julien Dilly   ORCID: orcid.org/0000-0002-4006-5285 9 , 10 ,
• Stephen A. Sastra 1 , 2 ,
• Carmine F. Palermo 1 , 2 ,
• Marie C. Hasselluhn   ORCID: orcid.org/0000-0001-9765-4075 1 , 2 ,
• Amanda R. Decker-Farrell 1 , 2 ,
• Stephanie Chang   ORCID: orcid.org/0009-0000-2026-5215 3 ,
• Lingyan Jiang 3 ,
• Xing Wei 3 ,
• Yu C. Yang 3 ,
• Ciara Helland 3 ,
• Haley Courtney 3 ,
• Yevgeniy Gindin 3 ,
• Karl Muonio 3 ,
• Ruiping Zhao 3 ,
• Samantha B. Kemp 5 ,
• Cynthia Clendenin   ORCID: orcid.org/0000-0003-4535-2088 11 ,
• Rina Sor   ORCID: orcid.org/0000-0003-2042-5746 11 ,
• William P. Vostrejs   ORCID: orcid.org/0000-0002-1659-0186 5 ,
• Priya S. Hibshman 4 ,
• Amber M. Amparo   ORCID: orcid.org/0000-0003-3805-746X 7 ,
• Connor Hennessey 9 , 10 ,
• Matthew G. Rees   ORCID: orcid.org/0000-0002-2987-7581 12 ,
• Melissa M. Ronan   ORCID: orcid.org/0000-0003-4269-1404 12 ,
• Jennifer A. Roth   ORCID: orcid.org/0000-0002-5117-5586 12 ,
• Jens Brodbeck 3 ,
• Lorenzo Tomassoni 2 , 13 ,
• Basil Bakir 1 , 2 ,
• Nicholas D. Socci 14 ,
• Laura E. Herring   ORCID: orcid.org/0000-0003-4496-7312 15 ,
• Natalie K. Barker 15 ,
• Junning Wang 9 , 10 ,
• James M. Cleary 9 , 10 ,
• Brian M. Wolpin   ORCID: orcid.org/0000-0002-0455-1032 9 , 10 ,
• John A. Chabot 16 ,
• Michael D. Kluger 16 ,
• Gulam A. Manji 1 , 2 ,
• Kenneth Y. Tsai   ORCID: orcid.org/0000-0001-5325-212X 17 ,
• Miroslav Sekulic 18 ,
• Stephen M. Lagana 18 ,
• Andrea Califano 1 , 2 , 13 , 19 , 20 , 21 , 22 , 23 ,
• Elsa Quintana 3 ,
• Zhengping Wang 3 ,
• Jacqueline A. M. Smith   ORCID: orcid.org/0000-0001-5028-8725 3 ,
• Matthew Holderfield 3 ,
• David Wildes   ORCID: orcid.org/0009-0009-3855-7270 3 ,
• Scott W. Lowe   ORCID: orcid.org/0000-0002-5284-9650 6 , 24 ,
• Michael A. Badgley 1 , 2 ,
• Andrew J. Aguirre   ORCID: orcid.org/0000-0002-0701-6203 9 , 10 , 12 , 25 ,
• Robert H. Vonderheide   ORCID: orcid.org/0000-0002-7252-954X 5 , 11 , 26 ,
• Ben Z. Stanger   ORCID: orcid.org/0000-0003-0410-4037 5 , 11 ,
• Timour Baslan 27 ,
• Channing J. Der   ORCID: orcid.org/0000-0002-7751-2747 7 , 8 ,
• Mallika Singh 3 &
• Kenneth P. Olive   ORCID: orcid.org/0000-0002-3392-8994 1 , 2  

Nature ( 2024 ) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

• Pancreatic cancer
• Pharmacodynamics

Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations 1,2 . RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants (RAS(ON) multi-selective) 3 . As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS 4 , we assessed the therapeutic potential of the RAS(ON) multi-selective inhibitor RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumor activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo . Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumors identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro . Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

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Author information

These authors contributed equally: Urszula N. Wasko, Jingjing Jiang

Authors and Affiliations

Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA

Urszula N. Wasko, Tanner C. Dalton, Alvaro Curiel-Garcia, Stephen A. Sastra, Carmine F. Palermo, Marie C. Hasselluhn, Amanda R. Decker-Farrell, Basil Bakir, Gulam A. Manji, Andrea Califano, Michael A. Badgley & Kenneth P. Olive

Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA

Urszula N. Wasko, Tanner C. Dalton, Alvaro Curiel-Garcia, Stephen A. Sastra, Carmine F. Palermo, Marie C. Hasselluhn, Amanda R. Decker-Farrell, Lorenzo Tomassoni, Basil Bakir, Gulam A. Manji, Andrea Califano, Michael A. Badgley & Kenneth P. Olive

Revolution Medicines, Inc., Redwood City, CA, USA

Jingjing Jiang, Yingyun Wang, Bianca Lee, Marie Menard, Stephanie Chang, Lingyan Jiang, Xing Wei, Yu C. Yang, Ciara Helland, Haley Courtney, Yevgeniy Gindin, Karl Muonio, Ruiping Zhao, Jens Brodbeck, Elsa Quintana, Zhengping Wang, Jacqueline A. M. Smith, Matthew Holderfield, David Wildes & Mallika Singh

Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

A. Cole Edwards & Priya S. Hibshman

University of Pennsylvania Perelman School of Medicine, Department of Medicine, Philadelphia, PA, USA

Margo Orlen, Samantha B. Kemp, William P. Vostrejs, Robert H. Vonderheide & Ben Z. Stanger

Cancer Biology & Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Sha Tian & Scott W. Lowe

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Clint A. Stalnecker, Kristina Drizyte-Miller, Amber M. Amparo & Channing J. Der

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Clint A. Stalnecker & Channing J. Der

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

Julien Dilly, Connor Hennessey, Junning Wang, James M. Cleary, Brian M. Wolpin & Andrew J. Aguirre

Harvard Medical School, Boston, MA, USA

University of Pennsylvania Perelman School of Medicine, Abramson Cancer Center, Philadelphia, PA, USA

Cynthia Clendenin, Rina Sor, Robert H. Vonderheide & Ben Z. Stanger

The Broad Institute of Harvard and MIT, Cambridge, MA, USA

Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth & Andrew J. Aguirre

Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA

Lorenzo Tomassoni & Andrea Califano

Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Nicholas D. Socci

UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Laura E. Herring & Natalie K. Barker

Department of Surgery, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA

John A. Chabot & Michael D. Kluger

Departments of Pathology, Tumor Microenvironment and Metastasis; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

Kenneth Y. Tsai

Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA

Miroslav Sekulic & Stephen M. Lagana

Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

Andrea Califano

J.P. Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA

Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA

Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA

Chan Zuckerberg Biohub New York, New York, NY, USA

Howard Hughes Medical Institute, Chevy Chase, MD, USA

Scott W. Lowe

Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

Andrew J. Aguirre

Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA

Robert H. Vonderheide

Department of Biomedical Sciences, School of Veterinary Medicine, The University of Pennsylvania, Philadelphia, PA, USA

Timour Baslan

You can also search for this author in PubMed   Google Scholar

Corresponding authors

Correspondence to Mallika Singh or Kenneth P. Olive .

Supplementary information

Supplementary figure 1.

uncropped Western Blot images with marked areas of interest, and target molecular weight.

Reporting Summary

Supplementary tables.

This file contains Supplementary Tables 1-10.

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Wasko, U.N., Jiang, J., Dalton, T.C. et al. Tumor-selective activity of RAS-GTP inhibition in pancreatic cancer. Nature (2024). https://doi.org/10.1038/s41586-024-07379-z

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Received : 18 July 2023

Accepted : 02 April 2024

Published : 08 April 2024

DOI : https://doi.org/10.1038/s41586-024-07379-z

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