A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer

Abstract Resistance to drugs targeting the androgen receptor (AR) signaling axis remains an important challenge in the treatment of prostate cancer patients. Activation of alternative growth pathways is one mechanism used by cancer cells to proliferate despite treatment, conferring drug resistance....

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Sander A. L. Palit, Jeroen van Dorp, Daniel Vis, Cor Lieftink, Simon Linder, Roderick Beijersbergen, Andries M. Bergman, Wilbert Zwart, Michiel S. van der Heijden
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/397d23f9500a43ac881b9b8bb5c1a817
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:397d23f9500a43ac881b9b8bb5c1a817
record_format	dspace
spelling	oai:doaj.org-article:397d23f9500a43ac881b9b8bb5c1a8172021-12-02T18:18:59ZA kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer10.1038/s41598-021-93107-w2045-2322https://doaj.org/article/397d23f9500a43ac881b9b8bb5c1a8172021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93107-whttps://doaj.org/toc/2045-2322Abstract Resistance to drugs targeting the androgen receptor (AR) signaling axis remains an important challenge in the treatment of prostate cancer patients. Activation of alternative growth pathways is one mechanism used by cancer cells to proliferate despite treatment, conferring drug resistance. Through a kinome-centered CRISPR-Cas9 screen in CWR-R1 prostate cancer cells, we identified activated BRAF signaling as a determinant for enzalutamide resistance. Combined pharmaceutical targeting of AR and MAPK signaling resulted in strong synergistic inhibition of cell proliferation. The association between BRAF activation and enzalutamide resistance was confirmed in two metastatic prostate cancer patients harboring activating mutations in the BRAF gene, as both patients were unresponsive to enzalutamide. Our findings suggest that co-targeting of the MAPK and AR pathways may be effective in patients with an activated MAPK pathway, particularly in patients harboring oncogenic BRAF mutations. These results warrant further investigation of the response to AR inhibitors in BRAF-mutated prostate tumors in clinical settings.Sander A. L. PalitJeroen van DorpDaniel VisCor LieftinkSimon LinderRoderick BeijersbergenAndries M. BergmanWilbert ZwartMichiel S. van der HeijdenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sander A. L. Palit Jeroen van Dorp Daniel Vis Cor Lieftink Simon Linder Roderick Beijersbergen Andries M. Bergman Wilbert Zwart Michiel S. van der Heijden A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer
description	Abstract Resistance to drugs targeting the androgen receptor (AR) signaling axis remains an important challenge in the treatment of prostate cancer patients. Activation of alternative growth pathways is one mechanism used by cancer cells to proliferate despite treatment, conferring drug resistance. Through a kinome-centered CRISPR-Cas9 screen in CWR-R1 prostate cancer cells, we identified activated BRAF signaling as a determinant for enzalutamide resistance. Combined pharmaceutical targeting of AR and MAPK signaling resulted in strong synergistic inhibition of cell proliferation. The association between BRAF activation and enzalutamide resistance was confirmed in two metastatic prostate cancer patients harboring activating mutations in the BRAF gene, as both patients were unresponsive to enzalutamide. Our findings suggest that co-targeting of the MAPK and AR pathways may be effective in patients with an activated MAPK pathway, particularly in patients harboring oncogenic BRAF mutations. These results warrant further investigation of the response to AR inhibitors in BRAF-mutated prostate tumors in clinical settings.
format	article
author	Sander A. L. Palit Jeroen van Dorp Daniel Vis Cor Lieftink Simon Linder Roderick Beijersbergen Andries M. Bergman Wilbert Zwart Michiel S. van der Heijden
author_facet	Sander A. L. Palit Jeroen van Dorp Daniel Vis Cor Lieftink Simon Linder Roderick Beijersbergen Andries M. Bergman Wilbert Zwart Michiel S. van der Heijden
author_sort	Sander A. L. Palit
title	A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer
title_short	A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer
title_full	A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer
title_fullStr	A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer
title_full_unstemmed	A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer
title_sort	kinome-centered crispr-cas9 screen identifies activated braf to modulate enzalutamide resistance with potential therapeutic implications in braf-mutated prostate cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/397d23f9500a43ac881b9b8bb5c1a817
work_keys_str_mv	AT sanderalpalit akinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT jeroenvandorp akinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT danielvis akinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT corlieftink akinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT simonlinder akinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT roderickbeijersbergen akinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT andriesmbergman akinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT wilbertzwart akinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT michielsvanderheijden akinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT sanderalpalit kinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT jeroenvandorp kinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT danielvis kinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT corlieftink kinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT simonlinder kinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT roderickbeijersbergen kinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT andriesmbergman kinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT wilbertzwart kinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer AT michielsvanderheijden kinomecenteredcrisprcas9screenidentifiesactivatedbraftomodulateenzalutamideresistancewithpotentialtherapeuticimplicationsinbrafmutatedprostatecancer
_version_	1718378148468359168

A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer

Ejemplares similares