ena-STUDY-NETHERLANDS CANCER INSTITUTE-10-03-2018-17:22:04:218-343
Transcriptomics and transposon mutagenesis identify multiple in vivo mechanisms of resistance to the FGFR inhibitor AZD4547
In human cancers, fibroblast growth factor receptor (FGFR) signaling is frequently hyper-activated by deregulation of FGF ligands or by activating mutations in the FGFR receptors, such as gene amplifications, point mutations and gene fusions. As such, FGFR inhibitors are considered to be an attractive therapeutic strategy for patients with mutations in FGFR family members. In previous work, we identified Fgfr2 as a key driver of invasive lobular carcinoma (ILC) in an in vivo insertional mutagenesis screen using the Sleeping Beauty (SB) transposon system. Here, we explore whether these FGFR-driven ILCs are sensitive to the FGFR inhibitor AZD4547 and use transposon mutagenesis in these tumors to identify potential therapy resistance mechanisms. Combined with RNA sequencing-based analyses of the AZD4547-resistant tumors, our in vivo approach identified several known and novel resistance mechanisms to FGFR inhibition, including mutations in the tyrosine kinase domain of FGFR2, overexpression of MET, inactivation of RASA1 and activation of the drug-efflux transporter ABCG2. Notably, ABCG2 and RASA1 were only identified from de novo transposon insertions acquired during AZD4547 treatment, demonstrating that insertional mutagenesis in mice is an effective tool for identifying resistance mechanisms to targeted cancer therapies. Finally, as most of the observed resistance mechanisms converge on reactivation of the canonical MAPK/ERK signaling cascade, our work indicates that combining FGFR- and MEK/ERK-inhibitors might overcome resistance to FGFR-targeted therapies.
In human cancers, fibroblast growth factor receptor (FGFR) signaling is frequently hyper-activated by deregulation of FGF ligands or by activating mutations in the FGFR receptors, such as gene amplifications, point mutations and gene fusions. As such, FGFR inhibitors are considered to be an attractive therapeutic strategy for patients with mutations in FGFR family members. In previous work, we identified Fgfr2 as a key driver of invasive lobular carcinoma (ILC) in an in vivo insertional mutagenesis screen using the Sleeping Beauty (SB) transposon system. Here, we explore whether these FGFR-driven ILCs are sensitive to the FGFR inhibitor AZD4547 and use transposon mutagenesis in these tumors to identify potential therapy resistance mechanisms. Combined with RNA sequencing-based analyses of the AZD4547-resistant tumors, our in vivo approach identified several known and novel resistance mechanisms to FGFR inhibition, including mutations in the tyrosine kinase domain of FGFR2, overexpression of MET, inactivation of RASA1 and activation of the drug-efflux transporter ABCG2. Notably, ABCG2 and RASA1 were only identified from de novo transposon insertions acquired during AZD4547 treatment, demonstrating that insertional mutagenesis in mice is an effective tool for identifying resistance mechanisms to targeted cancer therapies. Finally, as most of the observed resistance mechanisms converge on reactivation of the canonical MAPK/ERK signaling cascade, our work indicates that combining FGFR- and MEK/ERK-inhibitors might overcome resistance to FGFR-targeted therapies.