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Genetic and compound screens uncover factors modulating cancer cell response to indisulam

Discovering biomarkers of drug response and finding powerful drug combinations can support the reuse of previously abandoned cancer drugs in the clinic. Indisulam is an abandoned drug that acts as a molecular glue, inducing degradation of splicing factor RBM39 through interaction with CRL4(DCAF15)....

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Autores principales: Pogacar, Ziva, Groot, Kelvin, Jochems, Fleur, Dos Santos Dias, Matheus, Mulero-Sánchez, Antonio, Morris, Ben, Roosen, Mieke, Wardak, Leyma, De Conti, Giulia, Velds, Arno, Lieftink, Cor, Thijssen, Bram, Beijersbergen, Roderick L, Bernards, René, Leite de Oliveira, Rodrigo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9095732/
https://www.ncbi.nlm.nih.gov/pubmed/35534224
http://dx.doi.org/10.26508/lsa.202101348
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author Pogacar, Ziva
Groot, Kelvin
Jochems, Fleur
Dos Santos Dias, Matheus
Mulero-Sánchez, Antonio
Morris, Ben
Roosen, Mieke
Wardak, Leyma
De Conti, Giulia
Velds, Arno
Lieftink, Cor
Thijssen, Bram
Beijersbergen, Roderick L
Bernards, René
Leite de Oliveira, Rodrigo
author_facet Pogacar, Ziva
Groot, Kelvin
Jochems, Fleur
Dos Santos Dias, Matheus
Mulero-Sánchez, Antonio
Morris, Ben
Roosen, Mieke
Wardak, Leyma
De Conti, Giulia
Velds, Arno
Lieftink, Cor
Thijssen, Bram
Beijersbergen, Roderick L
Bernards, René
Leite de Oliveira, Rodrigo
author_sort Pogacar, Ziva
collection PubMed
description Discovering biomarkers of drug response and finding powerful drug combinations can support the reuse of previously abandoned cancer drugs in the clinic. Indisulam is an abandoned drug that acts as a molecular glue, inducing degradation of splicing factor RBM39 through interaction with CRL4(DCAF15). Here, we performed genetic and compound screens to uncover factors mediating indisulam sensitivity and resistance. First, a dropout CRISPR screen identified SRPK1 loss as a synthetic lethal interaction with indisulam that can be exploited therapeutically by the SRPK1 inhibitor SPHINX31. Moreover, a CRISPR resistance screen identified components of the degradation complex that mediate resistance to indisulam: DCAF15, DDA1, and CAND1. Last, we show that cancer cells readily acquire spontaneous resistance to indisulam. Upon acquiring indisulam resistance, pancreatic cancer (Panc10.05) cells still degrade RBM39 and are vulnerable to BCL-xL inhibition. The better understanding of the factors that influence the response to indisulam can assist rational reuse of this drug in the clinic.
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spelling pubmed-90957322022-05-23 Genetic and compound screens uncover factors modulating cancer cell response to indisulam Pogacar, Ziva Groot, Kelvin Jochems, Fleur Dos Santos Dias, Matheus Mulero-Sánchez, Antonio Morris, Ben Roosen, Mieke Wardak, Leyma De Conti, Giulia Velds, Arno Lieftink, Cor Thijssen, Bram Beijersbergen, Roderick L Bernards, René Leite de Oliveira, Rodrigo Life Sci Alliance Research Articles Discovering biomarkers of drug response and finding powerful drug combinations can support the reuse of previously abandoned cancer drugs in the clinic. Indisulam is an abandoned drug that acts as a molecular glue, inducing degradation of splicing factor RBM39 through interaction with CRL4(DCAF15). Here, we performed genetic and compound screens to uncover factors mediating indisulam sensitivity and resistance. First, a dropout CRISPR screen identified SRPK1 loss as a synthetic lethal interaction with indisulam that can be exploited therapeutically by the SRPK1 inhibitor SPHINX31. Moreover, a CRISPR resistance screen identified components of the degradation complex that mediate resistance to indisulam: DCAF15, DDA1, and CAND1. Last, we show that cancer cells readily acquire spontaneous resistance to indisulam. Upon acquiring indisulam resistance, pancreatic cancer (Panc10.05) cells still degrade RBM39 and are vulnerable to BCL-xL inhibition. The better understanding of the factors that influence the response to indisulam can assist rational reuse of this drug in the clinic. Life Science Alliance LLC 2022-05-09 /pmc/articles/PMC9095732/ /pubmed/35534224 http://dx.doi.org/10.26508/lsa.202101348 Text en © 2022 Pogacar et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Pogacar, Ziva
Groot, Kelvin
Jochems, Fleur
Dos Santos Dias, Matheus
Mulero-Sánchez, Antonio
Morris, Ben
Roosen, Mieke
Wardak, Leyma
De Conti, Giulia
Velds, Arno
Lieftink, Cor
Thijssen, Bram
Beijersbergen, Roderick L
Bernards, René
Leite de Oliveira, Rodrigo
Genetic and compound screens uncover factors modulating cancer cell response to indisulam
title Genetic and compound screens uncover factors modulating cancer cell response to indisulam
title_full Genetic and compound screens uncover factors modulating cancer cell response to indisulam
title_fullStr Genetic and compound screens uncover factors modulating cancer cell response to indisulam
title_full_unstemmed Genetic and compound screens uncover factors modulating cancer cell response to indisulam
title_short Genetic and compound screens uncover factors modulating cancer cell response to indisulam
title_sort genetic and compound screens uncover factors modulating cancer cell response to indisulam
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9095732/
https://www.ncbi.nlm.nih.gov/pubmed/35534224
http://dx.doi.org/10.26508/lsa.202101348
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