title: Gene Expression Ratios Lead to Accurate and Translatable Predictors of DR5 Agonism across Multiple Tumor Lineages.
abstract: Death Receptor 5 (DR5) agonists demonstrate anti-tumor activity in preclinical models but have yet to demonstrate robust clinical responses. A key limitation may be the lack of patient selection strategies to identify those most likely to respond to treatment. To overcome this limitation, we screened a DR5 agonist Nanobody across >600 cell lines representing 21 tumor lineages and assessed molecular features associated with response. High expression of DR5 and Casp8 were significantly associated with sensitivity, but their expression thresholds were difficult to translate due to low dynamic ranges. To address the translational challenge of establishing thresholds of gene expression, we developed a classifier based on ratios of genes that predicted response across lineages. The ratio classifier outperformed the DR5+Casp8 classifier, as well as standard approaches for feature selection and classification using genes, instead of ratios. This classifier was independently validated using 11 primary patient-derived pancreatic xenograft models showing perfect predictions as well as a striking linearity between prediction probability and anti-tumor response. A network analysis of the genes in the ratio classifier captured important biological relationships mediating drug response, specifically identifying key positive and negative regulators of DR5 mediated apoptosis, including DR5, CASP8, BID, cFLIP, XIAP and PEA15. Importantly, the ratio classifier shows translatability across gene expression platforms (from Affymetrix microarrays to RNA-seq) and across model systems (in vitro to in vivo). Our approach of using gene expression ratios presents a robust and novel method for constructing translatable biomarkers of compound response, which can also probe the underlying biology of treatment response.
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Anupama
authors.initials: A
authors.lastname: Reddy
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Growney
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Nick S
authors.initials: NS
authors.lastname: Wilson
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Emery
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ward
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Kelli A
authors.initials: KA
authors.lastname: Monaco
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Korn
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: John E
authors.initials: JE
authors.lastname: Monahan
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Stump
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Felipa A
authors.initials: FA
authors.lastname: Mapa
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wilson
authors.affiliation: Horizon CombinatoRx, Cambridge, MA, United States of America.
authors.forename: Janine
authors.initials: J
authors.lastname: Steiger
authors.affiliation: Horizon CombinatoRx, Cambridge, MA, United States of America.
authors.forename: Jebediah
authors.initials: J
authors.lastname: Ledell
authors.affiliation: Horizon CombinatoRx, Cambridge, MA, United States of America.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rickles
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Vic E
authors.initials: VE
authors.lastname: Myer
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Seth A
authors.initials: SA
authors.lastname: Ettenberg
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Schlegel
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Huet
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lehár
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053181:Caspase 8 / Q000235:genetics; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000235:genetics*; D014176:Protein Biosynthesis / Q000235:genetics*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505530:CASP8 protein, human; D053181:Caspase 8