DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies CREBBP as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC)
The development of predictive biomarkers of response to targeted therapies is an unmet clinical need for many antitumoral agents. Recent genome-wide loss-of-function screens, such as RNA interference (RNAi) and CRISPR-Cas9 libraries, are an unprecedented resource to identify novel drug targets, r...
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| Format: | info:eu-repo/semantics/article |
| Language: | eng |
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2023
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| Online Access: | https://hdl.handle.net/10171/66304 |
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| author | Carazo-Melo, F.(Fernando) Bertolo, C. (Cristina) Castilla, C. (Carlos) Cendoya-Garmendia, X. (Xabier) Campuzano, L. (Lucía) Serrano, D. (Diego) Gimeno, M. (Marian) Planes-Pedreño, F.J. (Francisco Javier) Pio, R. (Rubén) Montuenga-Badia, L.M. (Luis M.) Rubio, A. (Ángel) |
| author_facet | Carazo-Melo, F.(Fernando) Bertolo, C. (Cristina) Castilla, C. (Carlos) Cendoya-Garmendia, X. (Xabier) Campuzano, L. (Lucía) Serrano, D. (Diego) Gimeno, M. (Marian) Planes-Pedreño, F.J. (Francisco Javier) Pio, R. (Rubén) Montuenga-Badia, L.M. (Luis M.) Rubio, A. (Ángel) |
| author_sort | Carazo-Melo, F.(Fernando) |
| collection | DSpace |
| description | The development of predictive biomarkers of response to targeted therapies is an unmet
clinical need for many antitumoral agents. Recent genome-wide loss-of-function screens, such as
RNA interference (RNAi) and CRISPR-Cas9 libraries, are an unprecedented resource to identify
novel drug targets, reposition drugs and associate predictive biomarkers in the context of precision
oncology. In this work, we have developed and validated a large-scale bioinformatics tool named
DrugSniper, which exploits loss-of-function experiments to model the sensitivity of 6237 inhibitors
and predict their corresponding biomarkers of sensitivity in 30 tumor types. Applying DrugSniper to
small cell lung cancer (SCLC), we identified genes extensively explored in SCLC, such as Aurora
kinases or epigenetic agents. Interestingly, the analysis suggested a remarkable vulnerability to
polo-like kinase 1 (PLK1) inhibition in CREBBP-mutant SCLC cells. We validated this association
in vitro using four mutated and four wild-type SCLC cell lines and two PLK1 inhibitors (Volasertib
and BI2536), confirming that the effect of PLK1 inhibitors depended on the mutational status of
CREBBP. Besides, DrugSniper was validated in-silico with several known clinically-used treatments,
including the sensitivity of Tyrosine Kinase Inhibitors (TKIs) and Vemurafenib to FLT3 and BRAF
mutant cells, respectively. These findings show the potential of genome-wide loss-of-function screens
to identify new personalized therapeutic hypotheses in SCLC and potentially in other tumors, which
is a valuable starting point for further drug development and drug repositioning projects. |
| format | info:eu-repo/semantics/article |
| id | oai:dadun.unav.edu:10171-66304 |
| institution | Universidad de Navarra |
| language | eng |
| publishDate | 2023 |
| record_format | dspace |
| spelling | oai:dadun.unav.edu:10171-663042023-05-29T05:17:22Z DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies CREBBP as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC) Carazo-Melo, F.(Fernando) Bertolo, C. (Cristina) Castilla, C. (Carlos) Cendoya-Garmendia, X. (Xabier) Campuzano, L. (Lucía) Serrano, D. (Diego) Gimeno, M. (Marian) Planes-Pedreño, F.J. (Francisco Javier) Pio, R. (Rubén) Montuenga-Badia, L.M. (Luis M.) Rubio, A. (Ángel) Biomarker Small cell lung carcinoma SCLC CREBBP PLK1 Gene essentiality Drug; treatment DEMETER score RNAi Precision medicine Drug repositioning The development of predictive biomarkers of response to targeted therapies is an unmet clinical need for many antitumoral agents. Recent genome-wide loss-of-function screens, such as RNA interference (RNAi) and CRISPR-Cas9 libraries, are an unprecedented resource to identify novel drug targets, reposition drugs and associate predictive biomarkers in the context of precision oncology. In this work, we have developed and validated a large-scale bioinformatics tool named DrugSniper, which exploits loss-of-function experiments to model the sensitivity of 6237 inhibitors and predict their corresponding biomarkers of sensitivity in 30 tumor types. Applying DrugSniper to small cell lung cancer (SCLC), we identified genes extensively explored in SCLC, such as Aurora kinases or epigenetic agents. Interestingly, the analysis suggested a remarkable vulnerability to polo-like kinase 1 (PLK1) inhibition in CREBBP-mutant SCLC cells. We validated this association in vitro using four mutated and four wild-type SCLC cell lines and two PLK1 inhibitors (Volasertib and BI2536), confirming that the effect of PLK1 inhibitors depended on the mutational status of CREBBP. Besides, DrugSniper was validated in-silico with several known clinically-used treatments, including the sensitivity of Tyrosine Kinase Inhibitors (TKIs) and Vemurafenib to FLT3 and BRAF mutant cells, respectively. These findings show the potential of genome-wide loss-of-function screens to identify new personalized therapeutic hypotheses in SCLC and potentially in other tumors, which is a valuable starting point for further drug development and drug repositioning projects. 2023-05-22T09:44:02Z 2023-05-22T09:44:02Z 2020 info:eu-repo/semantics/article https://hdl.handle.net/10171/66304 eng info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII)/PI17%2F00411/ES/POTENCIACION DE LA INMUNOTERAPIA FRENTE AL CANCER DE PULMON MEDIANTE LA MODULACION DE LA RESPUESTA TUMORAL INNATA info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI19%2F00098/ES/DESARROLLO DE NUEVAS HERRAMIENTAS MOLECULARES PARA EL MANEJO PERSONALIZADO DEL PACIENTE DE CANCER DE PULMON EN ESTADIO PRECOZ. info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110344RB-I00/ES/NUEVA APROXIMACION COMPUTACIONAL PARA PREDECIR LETALIDAD SINTETICA EN CANCER info:eu-repo/semantics/openAccess application/pdf |
| spellingShingle | Biomarker Small cell lung carcinoma SCLC CREBBP PLK1 Gene essentiality Drug; treatment DEMETER score RNAi Precision medicine Drug repositioning Carazo-Melo, F.(Fernando) Bertolo, C. (Cristina) Castilla, C. (Carlos) Cendoya-Garmendia, X. (Xabier) Campuzano, L. (Lucía) Serrano, D. (Diego) Gimeno, M. (Marian) Planes-Pedreño, F.J. (Francisco Javier) Pio, R. (Rubén) Montuenga-Badia, L.M. (Luis M.) Rubio, A. (Ángel) DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies CREBBP as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC) |
| title | DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies CREBBP as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC) |
| title_full | DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies CREBBP as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC) |
| title_fullStr | DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies CREBBP as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC) |
| title_full_unstemmed | DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies CREBBP as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC) |
| title_short | DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies CREBBP as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC) |
| title_sort | drugsniper, a tool to exploit loss-of-function screens, identifies crebbp as a predictive biomarker of volasertib in small cell lung carcinoma (sclc) |
| topic | Biomarker Small cell lung carcinoma SCLC CREBBP PLK1 Gene essentiality Drug; treatment DEMETER score RNAi Precision medicine Drug repositioning |
| url | https://hdl.handle.net/10171/66304 |
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