DrugSniper, a Tool to Exploit Loss-Of-Function Screens, Identifies CREBBP as a Predictive Biomarker of VOLASERTIB in Small Cell Lung Carcinoma (SCLC)

Abstract

<jats:p>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.</jats:p>

A 5-Genomic Mutation Signature Can Predict the Survival for Patients With NSCLC Receiving Atezolizumab

“…The 5-genomic mutation signature of our risk score model consisted of mutations in CREBBP, KEAP1, RAF1, STK11 and TP53. CREBBP, which encodes an acetyltransferase, has been frequently found to develop mutations in many tumor types (12)(13)(14). At present, there is no literature focusing on the relationship between the CREBBP mutation and immunotherapy outcomes.…”

Diagnostic and Predictive Biomarkers in Lung Cancer

“…Different chemotherapy schemes applied according to molecular biomarkers could offer new opportunities to patients with LCNEC. The study of Carazo and colleagues [ 14 ] reports an innovative genome-wide loss-of-function screen that may be useful for identifying biomarkers predictive of therapy response, especially for tumors with scarce therapeutic options. Applying this tool, the authors identified CREBBP-defective SCLC to be vulnerable to polo-like kinase 1 (PLK1) inhibition.…”