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A CRISPR screen identifies MAPK7 as a target for combination with MEK inhibition in KRAS mutant NSCLC

Mutant KRAS represents one of the most frequently observed oncogenes in NSCLC, yet no therapies are approved for tumors that express activated KRAS variants. While there is strong rationale for the use of MEK inhibitors to treat tumors with activated RAS/MAPK signaling, these have proven ineffective...

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Autores principales: Dompe, Nicholas, Klijn, Christiaan, Watson, Sara A., Leng, Katherine, Port, Jenna, Cuellar, Trinna, Watanabe, Colin, Haley, Benjamin, Neve, Richard, Evangelista, Marie, Stokoe, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005515/
https://www.ncbi.nlm.nih.gov/pubmed/29912950
http://dx.doi.org/10.1371/journal.pone.0199264
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author Dompe, Nicholas
Klijn, Christiaan
Watson, Sara A.
Leng, Katherine
Port, Jenna
Cuellar, Trinna
Watanabe, Colin
Haley, Benjamin
Neve, Richard
Evangelista, Marie
Stokoe, David
author_facet Dompe, Nicholas
Klijn, Christiaan
Watson, Sara A.
Leng, Katherine
Port, Jenna
Cuellar, Trinna
Watanabe, Colin
Haley, Benjamin
Neve, Richard
Evangelista, Marie
Stokoe, David
author_sort Dompe, Nicholas
collection PubMed
description Mutant KRAS represents one of the most frequently observed oncogenes in NSCLC, yet no therapies are approved for tumors that express activated KRAS variants. While there is strong rationale for the use of MEK inhibitors to treat tumors with activated RAS/MAPK signaling, these have proven ineffective clinically. We therefore implemented a CRISPR screening approach to identify novel agents to sensitize KRAS mutant NSCLC cells to MEK inhibitor treatment. This approach identified multiple components of the canonical RAS/MAPK pathway consistent with previous studies. In addition, we identified MAPK7 as a novel, strong hit and validated this finding using multiple orthogonal approaches including knockdown and pharmacological inhibition. We show that MAPK7 inhibition attenuates the re-activation of MAPK signaling occurring following long-term MEK inhibition, thereby illustrating that MAPK7 mediates pathway reactivation in the face of MEK inhibition. Finally, genetic knockdown of MAPK7 combined with the MEK inhibitor cobimetinib in a mutant KRAS NSCLC xenograft model to mediate improved tumor growth inhibition. These data highlight that MAPK7 represents a promising target for combination treatment with MEK inhibition in KRAS mutant NSCLC.
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spelling pubmed-60055152018-06-25 A CRISPR screen identifies MAPK7 as a target for combination with MEK inhibition in KRAS mutant NSCLC Dompe, Nicholas Klijn, Christiaan Watson, Sara A. Leng, Katherine Port, Jenna Cuellar, Trinna Watanabe, Colin Haley, Benjamin Neve, Richard Evangelista, Marie Stokoe, David PLoS One Research Article Mutant KRAS represents one of the most frequently observed oncogenes in NSCLC, yet no therapies are approved for tumors that express activated KRAS variants. While there is strong rationale for the use of MEK inhibitors to treat tumors with activated RAS/MAPK signaling, these have proven ineffective clinically. We therefore implemented a CRISPR screening approach to identify novel agents to sensitize KRAS mutant NSCLC cells to MEK inhibitor treatment. This approach identified multiple components of the canonical RAS/MAPK pathway consistent with previous studies. In addition, we identified MAPK7 as a novel, strong hit and validated this finding using multiple orthogonal approaches including knockdown and pharmacological inhibition. We show that MAPK7 inhibition attenuates the re-activation of MAPK signaling occurring following long-term MEK inhibition, thereby illustrating that MAPK7 mediates pathway reactivation in the face of MEK inhibition. Finally, genetic knockdown of MAPK7 combined with the MEK inhibitor cobimetinib in a mutant KRAS NSCLC xenograft model to mediate improved tumor growth inhibition. These data highlight that MAPK7 represents a promising target for combination treatment with MEK inhibition in KRAS mutant NSCLC. Public Library of Science 2018-06-18 /pmc/articles/PMC6005515/ /pubmed/29912950 http://dx.doi.org/10.1371/journal.pone.0199264 Text en © 2018 Dompe et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Dompe, Nicholas
Klijn, Christiaan
Watson, Sara A.
Leng, Katherine
Port, Jenna
Cuellar, Trinna
Watanabe, Colin
Haley, Benjamin
Neve, Richard
Evangelista, Marie
Stokoe, David
A CRISPR screen identifies MAPK7 as a target for combination with MEK inhibition in KRAS mutant NSCLC
title A CRISPR screen identifies MAPK7 as a target for combination with MEK inhibition in KRAS mutant NSCLC
title_full A CRISPR screen identifies MAPK7 as a target for combination with MEK inhibition in KRAS mutant NSCLC
title_fullStr A CRISPR screen identifies MAPK7 as a target for combination with MEK inhibition in KRAS mutant NSCLC
title_full_unstemmed A CRISPR screen identifies MAPK7 as a target for combination with MEK inhibition in KRAS mutant NSCLC
title_short A CRISPR screen identifies MAPK7 as a target for combination with MEK inhibition in KRAS mutant NSCLC
title_sort crispr screen identifies mapk7 as a target for combination with mek inhibition in kras mutant nsclc
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005515/
https://www.ncbi.nlm.nih.gov/pubmed/29912950
http://dx.doi.org/10.1371/journal.pone.0199264
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