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Integration of signaling pathway and bromodomain and extra-terminal domain inhibition for the treatment of mutant Kirsten rat sarcoma viral oncogene homolog cancer

Mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) is now a drugable oncogenic driver and the KRAS G12C variant responds clinically to sotorasib and adagrasib that covalently block the cysteine of the active center and inhibit downstream signaling and proliferation. Unfortunately, progression-...

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Autores principales: Hamilton, Gerhard, Stickler, Sandra, Rath, Barbara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Open Exploration Publishing 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10651355/
https://www.ncbi.nlm.nih.gov/pubmed/38023987
http://dx.doi.org/10.37349/etat.2023.00178
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author Hamilton, Gerhard
Stickler, Sandra
Rath, Barbara
author_facet Hamilton, Gerhard
Stickler, Sandra
Rath, Barbara
author_sort Hamilton, Gerhard
collection PubMed
description Mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) is now a drugable oncogenic driver and the KRAS G12C variant responds clinically to sotorasib and adagrasib that covalently block the cysteine of the active center and inhibit downstream signaling and proliferation. Unfortunately, progression-free survival (PFS) of lung cancer patients is only 5–6 months and no survival advantage has been found for sotorasib in comparison to docetaxel chemotherapy. Increased responses to KRAS inhibitors are tested in combination with the son of sevenless 1 (SOS1) inhibitors, upstream and downstream signaling modulators as well as chemotherapeutics. Some of these approaches are limited by toxicity to normal tissues and by diverse mechanisms of resistance. In essence, most of these attempts are directed to the inhibition of proliferation by impairment of the signal transduction pathways. The final target of KRAS-mediated growth stimulation is MYC in the cell nucleus that stimulates transcription of a host of genes. In detail, MYC alters genomic enhancer and super-enhancers of transcription that are frequently deregulated in cancer. Such enhancers can be targeted by bromodomain and extra-terminal (BET) inhibitors (BETi) or degraders and this review discusses whether integrated SOS1 inhibition and BET targeting of MYC synergizes against mutant KRAS tumor growth. BET degraders in the form of proteolysis-targeting chimeras (PROTACs) combined with BAY-293-mediated SOS1 inhibition revealed marked cytotoxic synergy against mutant KRAS cancer cells and may constitute a promising option for clinical treatment.
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spelling pubmed-106513552023-10-26 Integration of signaling pathway and bromodomain and extra-terminal domain inhibition for the treatment of mutant Kirsten rat sarcoma viral oncogene homolog cancer Hamilton, Gerhard Stickler, Sandra Rath, Barbara Explor Target Antitumor Ther Review Mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) is now a drugable oncogenic driver and the KRAS G12C variant responds clinically to sotorasib and adagrasib that covalently block the cysteine of the active center and inhibit downstream signaling and proliferation. Unfortunately, progression-free survival (PFS) of lung cancer patients is only 5–6 months and no survival advantage has been found for sotorasib in comparison to docetaxel chemotherapy. Increased responses to KRAS inhibitors are tested in combination with the son of sevenless 1 (SOS1) inhibitors, upstream and downstream signaling modulators as well as chemotherapeutics. Some of these approaches are limited by toxicity to normal tissues and by diverse mechanisms of resistance. In essence, most of these attempts are directed to the inhibition of proliferation by impairment of the signal transduction pathways. The final target of KRAS-mediated growth stimulation is MYC in the cell nucleus that stimulates transcription of a host of genes. In detail, MYC alters genomic enhancer and super-enhancers of transcription that are frequently deregulated in cancer. Such enhancers can be targeted by bromodomain and extra-terminal (BET) inhibitors (BETi) or degraders and this review discusses whether integrated SOS1 inhibition and BET targeting of MYC synergizes against mutant KRAS tumor growth. BET degraders in the form of proteolysis-targeting chimeras (PROTACs) combined with BAY-293-mediated SOS1 inhibition revealed marked cytotoxic synergy against mutant KRAS cancer cells and may constitute a promising option for clinical treatment. Open Exploration Publishing 2023 2023-10-26 /pmc/articles/PMC10651355/ /pubmed/38023987 http://dx.doi.org/10.37349/etat.2023.00178 Text en © The Author(s) 2023. https://creativecommons.org/licenses/by/4.0/This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Review
Hamilton, Gerhard
Stickler, Sandra
Rath, Barbara
Integration of signaling pathway and bromodomain and extra-terminal domain inhibition for the treatment of mutant Kirsten rat sarcoma viral oncogene homolog cancer
title Integration of signaling pathway and bromodomain and extra-terminal domain inhibition for the treatment of mutant Kirsten rat sarcoma viral oncogene homolog cancer
title_full Integration of signaling pathway and bromodomain and extra-terminal domain inhibition for the treatment of mutant Kirsten rat sarcoma viral oncogene homolog cancer
title_fullStr Integration of signaling pathway and bromodomain and extra-terminal domain inhibition for the treatment of mutant Kirsten rat sarcoma viral oncogene homolog cancer
title_full_unstemmed Integration of signaling pathway and bromodomain and extra-terminal domain inhibition for the treatment of mutant Kirsten rat sarcoma viral oncogene homolog cancer
title_short Integration of signaling pathway and bromodomain and extra-terminal domain inhibition for the treatment of mutant Kirsten rat sarcoma viral oncogene homolog cancer
title_sort integration of signaling pathway and bromodomain and extra-terminal domain inhibition for the treatment of mutant kirsten rat sarcoma viral oncogene homolog cancer
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10651355/
https://www.ncbi.nlm.nih.gov/pubmed/38023987
http://dx.doi.org/10.37349/etat.2023.00178
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