Tumour cell responses to new fibroblast growth factor receptor tyrosine kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of acquired resistance.

摘要: Fibroblast growth factor receptors (FGFRs) can act as driving oncoproteins in certain cancers, making them attractive drug targets. Here we have characterized tumour cell responses to two new inhibitors of FGFR1-3, AZ12908010 and the clinical candidate AZD4547, comparisons with well-characterized FGFR inhibitor PD173074. In a panel 16 human lines, anti-proliferative activity or AZD4547 was strongly linked presence deregulated signalling, indicating that addiction FGFRs provides therapeutic opportunity for selective intervention. Acquired resistance targeted tyrosine kinase is growing problem clinic but has not yet been explored inhibitors. To assess how FGFR-dependent cells adapt long-term inhibition, generated derivative KMS-11 myeloma line (FGFR(Y373C)) acquired (KMS-11R cells). Basal phosphorylated downstream signalling were constitutively elevated refractory KMS-11R cells. Sequencing FGFR3 revealed heterozygous mutation at gatekeeper residue, encoding FGFR3(V555M); consistent this, cross-resistant These results define selectivity efficacy identify secondary mechanism should be anticipated evaluation proceeds.