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  1. Article ; Online: Exploiting the therapeutic implications of KRAS inhibition on tumor immunity.

    Molina-Arcas, Miriam / Downward, Julian

    Cancer cell

    2024  Volume 42, Issue 3, Page(s) 338–357

    Abstract: Over the past decade, RAS oncogenic proteins have transitioned from being deemed undruggable to having two clinically approved drugs, with several more in advanced stages of development. Despite the initial benefit of KRAS-G12C inhibitors for patients ... ...

    Abstract Over the past decade, RAS oncogenic proteins have transitioned from being deemed undruggable to having two clinically approved drugs, with several more in advanced stages of development. Despite the initial benefit of KRAS-G12C inhibitors for patients with tumors harboring this mutation, the rapid emergence of drug resistance underscores the urgent need to synergize these inhibitors with other therapeutic approaches to improve outcomes. RAS mutant tumor cells can create an immunosuppressive tumor microenvironment (TME), suggesting an increased susceptibility to immunotherapies following RAS inhibition. This provides a rationale for combining RAS inhibitory drugs with immune checkpoint blockade (ICB). However, achieving this synergy in the clinical setting has proven challenging. Here, we explore how understanding the impact of RAS mutant tumor cells on the TME can guide innovative approaches to combining RAS inhibition with immunotherapies, review progress in both pre-clinical and clinical stages, and discuss challenges and future directions.
    MeSH term(s) Humans ; Proto-Oncogene Proteins p21(ras) ; Neoplasms ; Mutation ; Immunotherapy ; Tumor Microenvironment
    Chemical Substances Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; KRAS protein, human
    Language English
    Publishing date 2024-03-12
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccell.2024.02.012
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The Potency of a

    Molina-Arcas, Miriam / Downward, Julian

    The New England journal of medicine

    2022  Volume 386, Issue 26, Page(s) 2523–2525

    MeSH term(s) Genetic Variation/genetics ; Humans ; Mutation ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/pharmacology ; ras Proteins/genetics ; ras Proteins/pharmacology
    Chemical Substances KRAS protein, human ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; ras Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2022-06-29
    Publishing country United States
    Document type Journal Article
    ZDB-ID 207154-x
    ISSN 1533-4406 ; 0028-4793
    ISSN (online) 1533-4406
    ISSN 0028-4793
    DOI 10.1056/NEJMcibr2202981
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Facts and Hopes on RAS Inhibitors and Cancer Immunotherapy.

    Boumelha, Jesse / Molina-Arcas, Miriam / Downward, Julian

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2023  Volume 29, Issue 24, Page(s) 5012–5020

    Abstract: Although the past decade has seen great strides in the development of immunotherapies that reactivate the immune system against tumors, there have also been major advances in the discovery of drugs blocking oncogenic drivers of cancer growth. However, ... ...

    Abstract Although the past decade has seen great strides in the development of immunotherapies that reactivate the immune system against tumors, there have also been major advances in the discovery of drugs blocking oncogenic drivers of cancer growth. However, there has been very little progress in combining immunotherapies with drugs that target oncogenic driver pathways. Some of the most important oncogenes in human cancer encode RAS family proteins, although these have proven challenging to target. Recently drugs have been approved that inhibit a specific mutant form of KRAS: G12C. These have improved the treatment of patients with lung cancer harboring this mutation, but development of acquired drug resistance after initial responses has limited the impact on overall survival. Because of the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, targeted KRAS G12C inhibition can indirectly affect antitumor immunity, and does so without compromising the critical role of normal RAS proteins in immune cells. This serves as a rationale for combination with immune checkpoint blockade, which can provide additional combinatorial therapeutic benefit in some preclinical cancer models. However, in clinical trials, combination of KRAS G12C inhibitors with PD-(L)1 blockade has yet to show improved outcome, in part due to treatment toxicities. A greater understanding of how oncogenic KRAS drives immune evasion and how mutant-specific KRAS inhibition impacts the tumor microenvironment can lead to novel approaches to combining RAS inhibition with immunotherapies.
    MeSH term(s) Humans ; Proto-Oncogene Proteins p21(ras)/genetics ; Lung Neoplasms/drug therapy ; Antineoplastic Agents/therapeutic use ; Oncogenes ; Mutation ; Immunotherapy ; Tumor Microenvironment
    Chemical Substances Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Antineoplastic Agents
    Language English
    Publishing date 2023-08-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-22-3655
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4223: Show issues Location:
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  4. Article ; Online: RAS Synthetic Lethal Screens Revisited: Still Seeking the Elusive Prize?

    Downward, Julian

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2015  Volume 21, Issue 8, Page(s) 1802–1809

    Abstract: The RAS genes are critical oncogenic drivers activated by point mutation in some 20% of human malignancies. However, no pharmacologic approaches to targeting RAS proteins directly have yet succeeded, leading to suggestions that these proteins may be " ... ...

    Abstract The RAS genes are critical oncogenic drivers activated by point mutation in some 20% of human malignancies. However, no pharmacologic approaches to targeting RAS proteins directly have yet succeeded, leading to suggestions that these proteins may be "undruggable." This has led to two alternative indirect approaches to targeting RAS function in cancer. One has been to target RAS signaling pathways downstream at tractable enzymes such as kinases, particularly in combination. The other, which is the focus of this review, has been to seek targets that are essential in cells bearing an activated RAS oncogene, but not those without. This synthetic lethal approach, while rooted in ideas from invertebrate genetics, has been inspired most strongly by the successful use of PARP inhibitors, such as olaparib, in the clinic to treat BRCA defective cancers. Several large-scale screens have been carried out using RNA interference-mediated expression silencing to find genes that are uniquely essential to RAS-mutant but not wild-type cells. These screens have been notable for the low degree of overlap between their results, with the possible exception of proteasome components, and have yet to lead to successful new clinical approaches to the treatment of RAS-mutant cancers. Possible reasons for these disappointing results are discussed here, along with a reevaluation of the approaches taken. On the basis of experience to date, RAS synthetic lethality has so far fallen some way short of its original promise and remains unproven as an approach to finding effective new ways of tackling RAS-mutant cancers. Clin Cancer Res; 21(8); 1802-9. ©2015 AACR. See all articles in this CCR Focus section, "Targeting RAS-Driven Cancers."
    MeSH term(s) Animals ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Drug Discovery ; Genomics/methods ; Humans ; Molecular Targeted Therapy ; Mutation ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Oncogene Protein p21(ras)/genetics ; Oncogene Protein p21(ras)/metabolism ; Protein Binding ; Signal Transduction/drug effects
    Chemical Substances Carrier Proteins ; Oncogene Protein p21(ras) (EC 3.6.5.2)
    Language English
    Publishing date 2015-04-15
    Publishing country United States
    Document type Editorial ; Review
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-14-2180
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Addendum: Micro-CT acquisition and image processing to track and characterize pulmonary nodules in mice.

    Zaw Thin, May / Moore, Christopher / Snoeks, Thomas / Kalber, Tammy / Downward, Julian / Behrens, Axel

    Nature protocols

    2023  Volume 18, Issue 7, Page(s) 2399

    MeSH term(s) Mice ; Animals ; X-Ray Microtomography ; Lung/diagnostic imaging ; Lung Neoplasms/diagnostic imaging ; Image Processing, Computer-Assisted/methods
    Language English
    Publishing date 2023-04-24
    Publishing country England
    Document type Journal Article
    ZDB-ID 2244966-8
    ISSN 1750-2799 ; 1754-2189
    ISSN (online) 1750-2799
    ISSN 1754-2189
    DOI 10.1038/s41596-023-00838-3
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  6. Article ; Online: RAS's cloak of invincibility slips at last?

    Downward, Julian

    Cancer cell

    2014  Volume 25, Issue 1, Page(s) 5–6

    Abstract: KRAS is the most frequently activated oncogene in human cancer, but it has, so far, shrugged off all attempts to inhibit its function directly. However, a recent report provides an entirely new approach to blocking mutant KRAS with small molecules and ... ...

    Abstract KRAS is the most frequently activated oncogene in human cancer, but it has, so far, shrugged off all attempts to inhibit its function directly. However, a recent report provides an entirely new approach to blocking mutant KRAS with small molecules and has the added benefit of sparing the wild-type protein.
    Language English
    Publishing date 2014-01-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccr.2013.12.016
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  7. Article ; Online: Mutant KRAS at the Heart of Tumor Immune Evasion.

    van Maldegem, Febe / Downward, Julian

    Immunity

    2019  Volume 52, Issue 1, Page(s) 14–16

    Abstract: In the search for therapeutic combinations for the treatment of cancer, the pairing of targeted inhibitors of oncogenic driver pathways with immunotherapy has largely been overlooked. In Nature, Canon et al. (2019) describe how the novel KRAS-G12C ... ...

    Abstract In the search for therapeutic combinations for the treatment of cancer, the pairing of targeted inhibitors of oncogenic driver pathways with immunotherapy has largely been overlooked. In Nature, Canon et al. (2019) describe how the novel KRAS-G12C inhibitor AMG 510 can potentiate immune rejection in combination with immune checkpoint blockade.
    MeSH term(s) Antineoplastic Agents ; Humans ; Immunotherapy ; Neoplasms ; Proto-Oncogene Proteins p21(ras) ; Tumor Escape
    Chemical Substances Antineoplastic Agents ; KRAS protein, human ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
    Language English
    Publishing date 2019-12-12
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2019.12.013
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    Zs.A 4227: Show issues Location:
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  8. Article ; Online: Drugging the Undruggable: Advances on RAS Targeting in Cancer.

    Molina-Arcas, Miriam / Samani, Amit / Downward, Julian

    Genes

    2021  Volume 12, Issue 6

    Abstract: Around 20% of all malignancies harbour activating mutations in RAS isoforms. Despite this, there is a deficiency of RAS-targeting agents licensed for therapeutic use. The picomolar affinity of RAS for GTP, and the lack of suitable pockets for high- ... ...

    Abstract Around 20% of all malignancies harbour activating mutations in RAS isoforms. Despite this, there is a deficiency of RAS-targeting agents licensed for therapeutic use. The picomolar affinity of RAS for GTP, and the lack of suitable pockets for high-affinity small-molecule binding, precluded effective therapies despite decades of research. Recently, characterisation of the biochemical properties of KRAS-G12C along with discovery of its 'switch-II pocket' have allowed development of effective mutant-specific inhibitors. Currently seven KRAS-G12C inhibitors are in clinical trials and sotorasib has become the first one to be granted FDA approval. Here, we discuss historical efforts to target RAS directly and approaches to target RAS effector signalling, including combinations that overcome limitations of single-agent targeting. We also review pre-clinical and clinical evidence for the efficacy of KRAS-G12C inhibitor monotherapy followed by an illustration of combination therapies designed to overcome primary resistance and extend durability of response. Finally, we briefly discuss novel approaches to targeting non-G12C mutant isoforms.
    MeSH term(s) Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Humans ; Mutation ; Neoplasms/drug therapy ; Neoplasms/genetics ; ras Proteins/antagonists & inhibitors ; ras Proteins/genetics ; ras Proteins/metabolism
    Chemical Substances Antineoplastic Agents ; Enzyme Inhibitors ; ras Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2021-06-10
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2527218-4
    ISSN 2073-4425 ; 2073-4425
    ISSN (online) 2073-4425
    ISSN 2073-4425
    DOI 10.3390/genes12060899
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Targeting RAF: trials and tribulations.

    Downward, Julian

    Nature medicine

    2011  Volume 17, Issue 3, Page(s) 286–288

    MeSH term(s) Drug Resistance, Neoplasm ; Humans ; Mutation ; Neoplasms/drug therapy ; Neoplasms/genetics ; Protein Kinase Inhibitors/therapeutic use
    Chemical Substances Protein Kinase Inhibitors
    Language English
    Publishing date 2011-03-07
    Publishing country United States
    Document type News
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/nm0311-286
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    Zs.A 4212: Show issues Location:
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  10. Article ; Online: LKB1 depletion-mediated epithelial-mesenchymal transition induces fibroblast activation in lung fibrosis.

    Xu, Zijian / Davies, Elizabeth R / Yao, Liudi / Zhou, Yilu / Li, Juanjuan / Alzetani, Aiman / Marshall, Ben G / Hancock, David / Wallis, Tim / Downward, Julian / Ewing, Rob M / Davies, Donna E / Jones, Mark G / Wang, Yihua

    Genes & diseases

    2024  Volume 11, Issue 3, Page(s) 101065

    Abstract: The factors that determine fibrosis progression or normal tissue repair are largely unknown. We previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments ... ...

    Abstract The factors that determine fibrosis progression or normal tissue repair are largely unknown. We previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine signalling. Here, we report that liver kinase B1 (LKB1) inactivation in ATII cells inhibits autophagy and induces EMT as a consequence. In IPF lungs, this is caused by downregulation of
    Language English
    Publishing date 2024-01-11
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2821806-1
    ISSN 2352-3042 ; 2352-3042
    ISSN (online) 2352-3042
    ISSN 2352-3042
    DOI 10.1016/j.gendis.2023.06.034
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