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posted on 2023-03-31, 19:33 authored by Josine M. Quispel-Janssen, Jitendra Badhai, Laurel Schunselaar, Stacey Price, Jonathan Brammeld, Francesco Iorio, Krishna Kolluri, Matthew Garnett, Anton Berns, Paul Baas, Ultan McDermott, Jacques Neefjes, Constantine Alifrangis <p>Figure S1. A subset MPM cell lines respond to FGFR inhibition. A) AZD4547 at a fixed dose of 500nM and B) BGJ-398 at a fixed dose of 300nM. Figure S2. A subset of pleural fluid derived early passage primary cultures (EPL) respond to FGFR inhibition. Figure S3. BAP1 mutation status does not correlate fully with protein expression. Figure S4. BAP1 null cell lines show increased activity of multiple receptor tyrosine kinases. Figure S5. FGF9 activates FGFR3 and modulates growth and phenotype. Figure S6. Gene expression studies comparing H226 BAP1 C91 vs BAP1 wt construct cell line. Figure S7. xenograft Immunohistochemistry for ki67, Caspase 3 under various experimental conditions. Figure S8. Anchor based combination drug screen in MPM using Pi3 kinase inhibitor as anchor drug.</p>
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ARTICLE ABSTRACT
Purpose: Despite intense research, treatment options for patients with mesothelioma are limited and offer only modest survival advantage. We screened a large panel of compounds in multiple mesothelioma models and correlated sensitivity with a range of molecular features to detect biomarkers of drug response.Experimental design: We utilized a high-throughput chemical inhibitor screen in a panel of 889 cancer cell lines, including both immortalized and primary early-passage mesothelioma lines, alongside comprehensive molecular characterization using Illumina whole-exome sequencing, copy-number analysis and Affymetrix array whole transcriptome profiling. Subsequent validation was done using functional assays such as siRNA silencing and mesothelioma mouse xenograft models.Results: A subgroup of immortalized and primary MPM lines appeared highly sensitive to FGFR inhibition. None of these lines harbored genomic alterations of FGFR family members, but rather BAP1 protein loss was associated with enhanced sensitivity to FGFR inhibition. This was confirmed in an MPM mouse xenograft model and by BAP1 knockdown and overexpression in cell line models. Gene expression analyses revealed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18. BAP1 loss was associated with activation of MAPK signaling. These associations were confirmed in a cohort of MPM patient samples.Conclusions: A subgroup of mesotheliomas cell lines harbor sensitivity to FGFR inhibition. BAP1 protein loss enriches for this subgroup and could serve as a potential biomarker to select patients for FGFR inhibitor treatment. These data identify a clinically relevant MPM subgroup for consideration of FGFR therapeutics in future clinical studies. Clin Cancer Res; 24(1); 84–94. ©2017 AACR.
