Comprehensive Pharmacogenomic Profiling of Malignant Pleural Mesothelioma Identifies a Subgroup Sensitive to FGFR Inhibition

Abstract

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. 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. 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. 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. .

Establishment and characterization of CRISPR/Cas9‐mediated NF2−/− human mesothelial cell line: Molecular insight into fibroblast growth factor receptor 2 in malignant pleural mesothelioma

“…They also showed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18. 29 Taken together with these reports, our study indicates the possibility that the FGF-FGFR axis could play an important role in the molecular pathogenesis of MPM.…”

“…Recent data reported by The Cancer Genome Atlas lung squamous cell carcinoma project showed that the FGFR tyrosine kinases are some of the most frequently altered kinase families in lung squamous cell carcinoma . Interestingly, Quispel‐Janssen et al recently reported that a subgroup of immortalized and primary MPM lines appeared to be highly sensitive to FGFR inhibition. They also showed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18 .…”

“…Interestingly, Quispel‐Janssen et al recently reported that a subgroup of immortalized and primary MPM lines appeared to be highly sensitive to FGFR inhibition. They also showed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18 . Taken together with these reports, our study indicates the possibility that the FGF‐FGFR axis could play an important role in the molecular pathogenesis of MPM.…”

“…As therapy targeting the FGF-FGFR axis has emerged as a novel anticancer application in a panel of solid cancers, [27][28][29] we next focused on FGFR2, whose expression was found to increase in the NF2-KO MeT-5A cells ( Figure 5A). In addition, the phosphorylation levels of both ERK and JNK MAPKs, increased in the NF2-KO clones, whereas the level of p38 MAPK remained constant ( Figure 5A).…”

Bcl‐2 inhibitors enhance FGFR inhibitor‐induced mitochondrial‐dependent cell death in FGFR2‐mutant endometrial cancer

“…C,D). Significant cell death in the absence of caspase‐3/7 activity has been reported in several other FGFR‐dependent models including breast cancer (CAL51) (Sharpe et al ., ) and mesothelioma (H2810) (Quispel‐Janssen et al ., ). Although caspase and/or PARP cleavage following FGFR inhibition has been reported in several gastric and breast models (Kunii et al ., ; Pearson et al ., ), it has only been reported in one liver cell line (Hep3B) (Hagel et al ., ) and one lung cancer cell line (H1581) (Goke et al ., 2015a) with caspase‐independent death also being reported in the latter.…”