Fupan Yao1,2, Seyed Ali Madani Tonekaboni1,2, Zhaleh Safikhani1,2, Petr Smirnov1,2, Nehme El-Hachem3,4, Mark Freeman1, Venkata Satya Kumar Manem1,2, Benjamin Haibe-Kains1,2,5,6. 1. Princess Margaret Cancer Centre, Toronto, Ontario, Canada. 2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. 3. Integrative Systems Biology, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada. 4. Department of Medicine, University of Montreal, Montréal, Quebec, Canada. 5. Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. 6. Ontario Institute of Cancer Research, Toronto, Ontario, Canada.
Abstract
Objectives: We sought to investigate the tissue specificity of drug sensitivities in large-scale pharmacological studies and compare these associations to those found in drug clinical indications. Materials and Methods: We leveraged the curated cell line response data from PharmacoGx and applied an enrichment algorithm on drug sensitivity values' area under the drug dose-response curves (AUCs) with and without adjustment for general level of drug sensitivity. Results: We observed tissue specificity in 63% of tested drugs, with 8% of total interactions deemed significant (false discovery rate <0.05). By restricting the drug-tissue interactions to those with AUC > 0.2, we found that in 52% of interactions, the tissue was predictive of drug sensitivity (concordance index > 0.65). When compared with clinical indications, the observed overlap was weak (Matthew correlation coefficient, MCC = 0.0003, P > .10). Discussion: While drugs exhibit significant tissue specificity in vitro, there is little overlap with clinical indications. This can be attributed to factors such as underlying biological differences between in vitro models and patient tumors, or the inability of tissue-specific drugs to bring additional benefits beyond gold standard treatments during clinical trials. Conclusion: Our meta-analysis of pan-cancer drug screening datasets indicates that most tested drugs exhibit tissue-specific sensitivities in a large panel of cancer cell lines. However, the observed preclinical results do not translate to the clinical setting. Our results suggest that additional research into showing parallels between preclinical and clinical data is required to increase the translational potential of in vitro drug screening.
Objectives: We sought to investigate the tissue specificity of drug sensitivities in large-scale pharmacological studies and compare these associations to those found in drug clinical indications. Materials and Methods: We leveraged the curated cell line response data from PharmacoGx and applied an enrichment algorithm on drug sensitivity values' area under the drug dose-response curves (AUCs) with and without adjustment for general level of drug sensitivity. Results: We observed tissue specificity in 63% of tested drugs, with 8% of total interactions deemed significant (false discovery rate <0.05). By restricting the drug-tissue interactions to those with AUC > 0.2, we found that in 52% of interactions, the tissue was predictive of drug sensitivity (concordance index > 0.65). When compared with clinical indications, the observed overlap was weak (Matthew correlation coefficient, MCC = 0.0003, P > .10). Discussion: While drugs exhibit significant tissue specificity in vitro, there is little overlap with clinical indications. This can be attributed to factors such as underlying biological differences between in vitro models and patienttumors, or the inability of tissue-specific drugs to bring additional benefits beyond gold standard treatments during clinical trials. Conclusion: Our meta-analysis of pan-cancer drug screening datasets indicates that most tested drugs exhibit tissue-specific sensitivities in a large panel of cancer cell lines. However, the observed preclinical results do not translate to the clinical setting. Our results suggest that additional research into showing parallels between preclinical and clinical data is required to increase the translational potential of in vitro drug screening.
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