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Novel mutant KRAS addiction signature predicts response to the combination of ERBB and MEK inhibitors in lung and pancreatic cancers

KRAS mutations are prevalent in pancreatic and lung cancers, but not all mutant (mt) KRAS tumors are addicted to mt KRAS. Here, we discovered a 30-gene transcriptome signature “KDS30” that encodes a novel EGFR/ERBB2-driven signaling network and predicts mt KRAS, but not NRAS or HRAS, oncogene addict...

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Autores principales: Tyc, Katarzyna M., Kazi, Aslamuzzaman, Ranjan, Alok, Wang, Rui, Sebti, Said M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9958355/
https://www.ncbi.nlm.nih.gov/pubmed/36852277
http://dx.doi.org/10.1016/j.isci.2023.106082
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author Tyc, Katarzyna M.
Kazi, Aslamuzzaman
Ranjan, Alok
Wang, Rui
Sebti, Said M.
author_facet Tyc, Katarzyna M.
Kazi, Aslamuzzaman
Ranjan, Alok
Wang, Rui
Sebti, Said M.
author_sort Tyc, Katarzyna M.
collection PubMed
description KRAS mutations are prevalent in pancreatic and lung cancers, but not all mutant (mt) KRAS tumors are addicted to mt KRAS. Here, we discovered a 30-gene transcriptome signature “KDS30” that encodes a novel EGFR/ERBB2-driven signaling network and predicts mt KRAS, but not NRAS or HRAS, oncogene addiction. High KDS30 tumors from mt KRAS lung and pancreatic cancer patients are enriched in genes upregulated by EGFR, ERBB2, mt KRAS or MEK. EGFR/ERBB2 (neratinib) and MEK (cobimetinib) inhibitor combination inhibits tumor growth and prolongs mouse survival in high, but not low, KDS30 mt KRAS lung and pancreatic xenografts, and is synergistic only in high KDS30 mt KRAS patient-derived organoids. Furthermore, mt KRAS high KDS30 lung and pancreatic cancer patients live significantly shorter lives than those with low KDS30. Thus, KDS30 can identify lung and pancreatic cancer patients whose tumors are addicted to mt KRAS, and predicts EGFR/ERBB2 and MEK inhibitor combination response.
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spelling pubmed-99583552023-02-26 Novel mutant KRAS addiction signature predicts response to the combination of ERBB and MEK inhibitors in lung and pancreatic cancers Tyc, Katarzyna M. Kazi, Aslamuzzaman Ranjan, Alok Wang, Rui Sebti, Said M. iScience Article KRAS mutations are prevalent in pancreatic and lung cancers, but not all mutant (mt) KRAS tumors are addicted to mt KRAS. Here, we discovered a 30-gene transcriptome signature “KDS30” that encodes a novel EGFR/ERBB2-driven signaling network and predicts mt KRAS, but not NRAS or HRAS, oncogene addiction. High KDS30 tumors from mt KRAS lung and pancreatic cancer patients are enriched in genes upregulated by EGFR, ERBB2, mt KRAS or MEK. EGFR/ERBB2 (neratinib) and MEK (cobimetinib) inhibitor combination inhibits tumor growth and prolongs mouse survival in high, but not low, KDS30 mt KRAS lung and pancreatic xenografts, and is synergistic only in high KDS30 mt KRAS patient-derived organoids. Furthermore, mt KRAS high KDS30 lung and pancreatic cancer patients live significantly shorter lives than those with low KDS30. Thus, KDS30 can identify lung and pancreatic cancer patients whose tumors are addicted to mt KRAS, and predicts EGFR/ERBB2 and MEK inhibitor combination response. Elsevier 2023-01-31 /pmc/articles/PMC9958355/ /pubmed/36852277 http://dx.doi.org/10.1016/j.isci.2023.106082 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Tyc, Katarzyna M.
Kazi, Aslamuzzaman
Ranjan, Alok
Wang, Rui
Sebti, Said M.
Novel mutant KRAS addiction signature predicts response to the combination of ERBB and MEK inhibitors in lung and pancreatic cancers
title Novel mutant KRAS addiction signature predicts response to the combination of ERBB and MEK inhibitors in lung and pancreatic cancers
title_full Novel mutant KRAS addiction signature predicts response to the combination of ERBB and MEK inhibitors in lung and pancreatic cancers
title_fullStr Novel mutant KRAS addiction signature predicts response to the combination of ERBB and MEK inhibitors in lung and pancreatic cancers
title_full_unstemmed Novel mutant KRAS addiction signature predicts response to the combination of ERBB and MEK inhibitors in lung and pancreatic cancers
title_short Novel mutant KRAS addiction signature predicts response to the combination of ERBB and MEK inhibitors in lung and pancreatic cancers
title_sort novel mutant kras addiction signature predicts response to the combination of erbb and mek inhibitors in lung and pancreatic cancers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9958355/
https://www.ncbi.nlm.nih.gov/pubmed/36852277
http://dx.doi.org/10.1016/j.isci.2023.106082
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