E-TABM-1222 - Transcription profiling by array of wild-type and AX12908010-resistant human KMS11 cells to study the mechanism of acquired resistance to FGFR inhibitors
Released on 2 October 2012, last updated on 2 May 2014
Fibroblast growth factor receptors (FGFRs) can act as driving oncoproteins in certain cancers due to mutation, over-expression or activating gene fusions and are therefore attractive drug targets. Here we have characterized tumour cell responses to three new inhibitors of FGFR1-3, AZ12576089, AZ12908010 and the clinical candidate AZD4547, making comparisons with the well-characterized FGFR inhibitor PD173074. Using a panel of 16 human tumour cell lines we show that the anti-proliferative activity of AZ12908010 and AZD4547 is strongly linked to the presence of de-regulated FGFR signalling. In contrast, AZ12576089 was also able to inhibit proliferation of cells lacking de-regulated FGFR, suggesting off-target effects. Acquired resistance to targeted tyrosine kinase inhibitors (TKIs) is a growing problem in the clinic. To assess how FGFR-dependent tumour cells may adapt to long-term exposure to FGFR inhibitors we generated a derivative of the KMS-11 myeloma cell line (FGFRY373C) with acquired resistance to AZ12908010 (KMS-11R cells). Basal P-FGFR3, P-FRS2 and P-ERK1/2 and D-type cyclins were all inhibited by AZ12908010 in parental KMS-11 cells whereas these markers were constitutively elevated and refractory to drug in KMS-11R cells. Sequencing of FGFR3 in KMS-11R cells revealed the presence of a heterozygous mutation at the gatekeeper residue, encoding FGFR3V555M. Consistent with this KMS-11R cells were cross-resistant to AZD4547 and PD173074 but remained fully sensitive to AZ12576089, confirming that the anti-proliferative effects of AZ12576089 are not related to FGFR inhibition. These results define the selectivity and efficacy of two new FGFR inhibitors and identify a secondary gatekeeper mutation as a mechanism of acquired resistance to FGFR inhibitors that should be anticipated as clinical evaluation proceeds.
transcription profiling by array, genetic modification
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. Chell V, Balmanno K, Little AS, Wilson M, Andrews S, Blockley L, Hampson M, Gavine PR, Cook SJ. Oncogene. Aug(6) (2012), PMID:22869148