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      Targeting the untargetable KRAS in cancer therapy

      review-article
      Author(s): a , * , a , b
      Publication date (Electronic):
      Journal: Acta Pharmaceutica Sinica. B
      Publisher: Elsevier
      Keywords: KRAS, Oncogene, Mutation, Cancer, Inhibitor, Targeted therapy

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          Abstract

          RAS is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30% of all human cancers. As the most frequently mutated RAS isoform, KRAS is intensively studied in the past years. Despite its well-recognized importance in cancer malignancy, continuous efforts in the past three decades failed to develop approved therapies for KRAS mutant cancer. KRAS has thus long been considered to be undruggable. Encouragingly, recent studies have aroused renewed interest in the development of KRAS inhibitors either directly towards mutant KRAS or against the crucial steps required for KRAS activation. This review summarizes the most recent progress in the exploration of KRAS-targeted anticancer strategies and hopefully provides useful insights for the field.

          Graphical abstract

          Continuous efforts in the past three decades failed to develop approved therapies for KRAS mutant cancer. Encouragingly, recent progress in the development of KRAS inhibitors either directly towards mutant KRAS or against the crucial steps required for KRAS activation may bring breakthrough for this long-pursued undruggable target.

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          Most cited references36

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          Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer.

          Lauren J. Bayne, Gregory L. Beatty, Nirag C. Jhala … (2012)
          Cancer-associated inflammation is thought to be a barrier to immune surveillance, particularly in pancreatic ductal adenocarcinoma (PDA). Gr-1(+) CD11b(+) cells are a key feature of cancer inflammation in PDA, but remain poorly understood. Using a genetically engineered mouse model of PDA, we show that tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) is necessary and sufficient to drive the development of Gr-1(+) CD11b(+) cells that suppressed antigen-specific T cells. In vivo, abrogation of tumor-derived GM-CSF inhibited the recruitment of Gr-1(+) CD11b(+) cells to the tumor microenvironment and blocked tumor development-a finding that was dependent on CD8(+) T cells. In humans, PDA tumor cells prominently expressed GM-CSF in vivo. Thus, tumor-derived GM-CSF is an important regulator of inflammation and immune suppression within the tumor microenvironment. Copyright © 2012 Elsevier Inc. All rights reserved.
          Article 0 comments Cited 337 times – based on 0 reviews     Review now
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            The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants.

            K Scheffzek, M R Ahmadian, W Kabsch … (1997)
            The three-dimensional structure of the complex between human H-Ras bound to guanosine diphosphate and the guanosine triphosphatase (GTPase)-activating domain of the human GTPase-activating protein p120GAP (GAP-334) in the presence of aluminum fluoride was solved at a resolution of 2.5 angstroms. The structure shows the partly hydrophilic and partly hydrophobic nature of the communication between the two molecules, which explains the sensitivity of the interaction toward both salts and lipids. An arginine side chain (arginine-789) of GAP-334 is supplied into the active site of Ras to neutralize developing charges in the transition state. The switch II region of Ras is stabilized by GAP-334, thus allowing glutamine-61 of Ras, mutation of which activates the oncogenic potential, to participate in catalysis. The structural arrangement in the active site is consistent with a mostly associative mechanism of phosphoryl transfer and provides an explanation for the activation of Ras by glycine-12 and glutamine-61 mutations. Glycine-12 in the transition state mimic is within van der Waals distance of both arginine-789 of GAP-334 and glutamine-61 of Ras, and even its mutation to alanine would disturb the arrangements of residues in the transition state.
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              Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia.

              Yuliya Pylayeva-Gupta, Kyoung-Eun Lee, Cristina H. Hajdu … (2012)
              Stromal responses elicited by early stage neoplastic lesions can promote tumor growth. However, the molecular mechanisms that underlie the early recruitment of stromal cells to sites of neoplasia remain poorly understood. Here, we demonstrate an oncogenic Kras(G12D)-dependent upregulation of GM-CSF in mouse pancreatic ductal epithelial cells (PDECs). An enhanced GM-CSF production is also observed in human PanIN lesions. Kras(G12D)-dependent production of GM-CSF in vivo is required for the recruitment of Gr1(+)CD11b(+) myeloid cells. The suppression of GM-CSF production inhibits the in vivo growth of Kras(G12D)-PDECs, and, consistent with the role of GM-CSF in Gr1(+)CD11b(+) mobilization, this effect is mediated by CD8(+) T cells. These results identify a pathway that links oncogenic activation to the evasion of antitumor immunity. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Pingyu Liu
                Journal
                Journal ID (nlm-ta): Acta Pharm Sin B
                Journal ID (iso-abbrev): Acta Pharm Sin B
                Title: Acta Pharmaceutica Sinica. B
                Publisher: Elsevier
                ISSN (Print): 2211-3835
                ISSN (Electronic): 2211-3843
                Publication date PMC-release: 06 March 2019
                Publication date (Print): September 2019
                Publication date (Electronic): 06 March 2019
                Volume: 9
                Issue: 5
                Pages: 871-879
                Affiliations
                [a ]Pharmacy Department, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
                [b ]Department of Clinical Pharmacy, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
                Author notes
                [* ]Corresponding author. Tel.: +86 25 58509955. judy_liupy@ 123456163.com
                Article
                Publisher ID: S2211-3835(18)30958-4
                DOI: 10.1016/j.apsb.2019.03.002
                PMC ID: 6804475
                PubMed ID: 31649840
                SO-VID: 865a08ee-8479-4ebe-912d-316fa2403a4a
                Copyright © © 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 20 December 2018
                Date revision received : 29 January 2019
                Date accepted : 7 February 2019
                Categories
                Subject: Review

                Keywords: kras,oncogene,mutation,cancer,inhibitor,targeted therapy
                Data availability:
                Keywords: kras, oncogene, mutation, cancer, inhibitor, targeted therapy

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