DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies <i>CREBBP</i> 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, repo...
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MDPI AG
2020-07-01
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author | Fernando Carazo Cristina Bértolo Carlos Castilla Xabier Cendoya Lucía Campuzano Diego Serrano Marian Gimeno Francisco J. Planes Ruben Pio Luis M. Montuenga Angel Rubio |
author_facet | Fernando Carazo Cristina Bértolo Carlos Castilla Xabier Cendoya Lucía Campuzano Diego Serrano Marian Gimeno Francisco J. Planes Ruben Pio Luis M. Montuenga Angel Rubio |
author_sort | Fernando Carazo |
collection | DOAJ |
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 (<i>PLK1</i>) inhibition in <i>CREBBP</i>-mutant SCLC cells. We validated this association in vitro using four mutated and four wild-type SCLC cell lines and two <i>PLK1</i> inhibitors (Volasertib and BI2536), confirming that the effect of <i>PLK1</i> inhibitors depended on the mutational status of <i>CREBBP</i>. Besides, DrugSniper was validated in-silico with several known clinically-used treatments, including the sensitivity of Tyrosine Kinase Inhibitors (TKIs) and Vemurafenib to <i>FLT3</i> and <i>BRAF</i> 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. |
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spelling | doaj.art-61e84d302b684d56a8b7e5093c1a860d2023-11-20T06:05:35ZengMDPI AGCancers2072-66942020-07-01127182410.3390/cancers12071824DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies <i>CREBBP</i> as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC)Fernando Carazo0Cristina Bértolo1Carlos Castilla2Xabier Cendoya3Lucía Campuzano4Diego Serrano5Marian Gimeno6Francisco J. Planes7Ruben Pio8Luis M. Montuenga9Angel Rubio10Department of Biomedical Engineering and Sciences. School of Engineering, University of Navarra, 20018 San Sebastián, SpainProgram in Solid Tumors, Center for Applied Medical Research (CIMA), CIBERONC and Navarra’s Health Research Institute (IDISNA), 31008 Pamplona, SpainDepartment of Biomedical Engineering and Sciences. School of Engineering, University of Navarra, 20018 San Sebastián, SpainDepartment of Biomedical Engineering and Sciences. School of Engineering, University of Navarra, 20018 San Sebastián, SpainUniversity of Luxembourg, 4365 Esch-sur-Alzette, LuxembourgProgram in Solid Tumors, Center for Applied Medical Research (CIMA), CIBERONC and Navarra’s Health Research Institute (IDISNA), 31008 Pamplona, SpainDepartment of Biomedical Engineering and Sciences. School of Engineering, University of Navarra, 20018 San Sebastián, SpainDepartment of Biomedical Engineering and Sciences. School of Engineering, University of Navarra, 20018 San Sebastián, SpainProgram in Solid Tumors, Center for Applied Medical Research (CIMA), CIBERONC and Navarra’s Health Research Institute (IDISNA), 31008 Pamplona, SpainProgram in Solid Tumors, Center for Applied Medical Research (CIMA), CIBERONC and Navarra’s Health Research Institute (IDISNA), 31008 Pamplona, SpainDepartment of Biomedical Engineering and Sciences. School of Engineering, University of Navarra, 20018 San Sebastián, SpainThe 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 (<i>PLK1</i>) inhibition in <i>CREBBP</i>-mutant SCLC cells. We validated this association in vitro using four mutated and four wild-type SCLC cell lines and two <i>PLK1</i> inhibitors (Volasertib and BI2536), confirming that the effect of <i>PLK1</i> inhibitors depended on the mutational status of <i>CREBBP</i>. Besides, DrugSniper was validated in-silico with several known clinically-used treatments, including the sensitivity of Tyrosine Kinase Inhibitors (TKIs) and Vemurafenib to <i>FLT3</i> and <i>BRAF</i> 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.https://www.mdpi.com/2072-6694/12/7/1824biomarkersmall cell lung carcinomaSCLCCREBBPPLK1gene essentiality |
spellingShingle | Fernando Carazo Cristina Bértolo Carlos Castilla Xabier Cendoya Lucía Campuzano Diego Serrano Marian Gimeno Francisco J. Planes Ruben Pio Luis M. Montuenga Angel Rubio DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies <i>CREBBP</i> as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC) Cancers biomarker small cell lung carcinoma SCLC CREBBP PLK1 gene essentiality |
title | DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies <i>CREBBP</i> as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC) |
title_full | DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies <i>CREBBP</i> as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC) |
title_fullStr | DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies <i>CREBBP</i> 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 <i>CREBBP</i> as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC) |
title_short | DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies <i>CREBBP</i> as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC) |
title_sort | drugsniper a tool to exploit loss of function screens identifies i crebbp i as a predictive biomarker of volasertib in small cell lung carcinoma sclc |
topic | biomarker small cell lung carcinoma SCLC CREBBP PLK1 gene essentiality |
url | https://www.mdpi.com/2072-6694/12/7/1824 |
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