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Ref Type Journal Article
PMID (22869148)
Authors Chell V, Balmanno K, Little AS, Wilson M, Andrews S, Blockley L, Hampson M, Gavine PR, Cook SJ
Title 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.
Journal Oncogene
Vol 32
Issue 25
Date 2013 Jun 20
URL
Abstract Text 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, making comparisons with the well-characterized FGFR inhibitor PD173074. In a panel of 16 human tumour cell lines, the anti-proliferative activity of AZ12908010 or AZD4547 was strongly linked to the presence of deregulated FGFR signalling, indicating that addiction to deregulated FGFRs provides a therapeutic opportunity for selective intervention. Acquired resistance to targeted tyrosine kinase inhibitors is a growing problem in the clinic but has not yet been explored for FGFR inhibitors. To assess how FGFR-dependent tumour cells adapt to long-term FGFR inhibition, we generated a derivative of the KMS-11 myeloma cell line (FGFR(Y373C)) with acquired resistance to AZ12908010 (KMS-11R cells). Basal phosphorylated FGFR and FGFR-dependent downstream signalling 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 FGFR3(V555M); consistent with this, KMS-11R cells were cross-resistant to AZD4547 and PD173074. 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
AZ6089 AZ6089 1 0
AZ8010 AZ8010 7 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
AZ6089 AZ12576089 FGFR Inhibitor (Pan) 18 AZ6089 (AZ12576089) binds and inhibits FGFR1, 2, 3, and 4, which may result in the inhibition of FGFR mediated signal transduction pathways and inhibition of tumor cell proliferation (PMID: 22869148).
AZ8010 AZ12908010 FGFR1 Inhibitor 23 FGFR2 Inhibitor 16 FGFR3 Inhibitor 13 AZ12908010 (AZ8010) binds and inhibits FGFR1, 2, and 3, which may result in the inhibition of FGFR mediated signal transduction pathways and inhibition of tumor cell proliferation (PMID: 22869148).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 wild-type Advanced Solid Tumor predicted - sensitive AZ6089 Preclinical Actionable In a preclinical study, AZ12576089 (AZ6089) inhibited FGF2-induced ERK1/2 phosphorylation and cell proliferation in transformed fibroblasts in culture (PMID: 22869148). 22869148
FGFR3 over exp transitional cell carcinoma sensitive AZ8010 Preclinical Actionable In a preclinical study, AZ8010 inhibited proliferation of urothelial cancer cells with over expression of FGFR3 in culture (PMID: 22869148). 22869148
FGFR3 dec exp FGFR3 wild-type HRAS G12V transitional cell carcinoma resistant AZD4547 Preclinical Actionable In a preclinical study, urothelial cancer cells with low expression of wild-type FGFR3 that harbored HRAS G12V demonstrated resistance to AZD4547 in culture (PMID: 22869148). 22869148
FGFR3 dec exp FGFR3 wild-type HRAS G12V transitional cell carcinoma decreased response AZ8010 Preclinical Actionable In a preclinical study, urothelial cancer cells with low expression of wild-type FGFR3 that harbored HRAS G12V demonstrated resistance to AZ8010 in culture (PMID: 22869148). 22869148
FGFR2 amp stomach cancer sensitive AZD4547 Preclinical Actionable In a preclinical study, AZD4547 inhibited FGFR signaling, and decreased proliferation and induced cell-cycle arrest in gastric cancer cells with amplification and over expression of FGFR2 in culture (PMID: 22869148). 22869148
FGFR3 S249C FGFR3 over exp transitional cell carcinoma sensitive PD173074 Preclinical Actionable In a preclinical study, PD173074 inhibited growth of urothelial carcinoma (UC) cells expressing high levels of FGFR3 S249C, but had reduced efficacy against UC cells with low levels of FGFR3 S249C expression (PMID: 22869148). 22869148
FGFR3 Y373C FGFR3 over exp multiple myeloma sensitive PD173074 Preclinical Actionable In a preclinical study, PD173074 inhibited Fgfr3 signaling and decreased proliferation and survival of multiple myeloma cells over expressing FGFR3 Y373C in culture (PMID: 22869148). 22869148
FGFR3 dec exp FGFR3 wild-type HRAS G12V transitional cell carcinoma resistant PD173074 Preclinical Actionable In a preclinical study, urothelial cancer cells with low expression of wild-type FGFR3 that harbored HRAS G12V demonstrated resistance to PD173074 in culture (PMID: 22869148). 22869148
FGFR3 G384D FGFR3 over exp multiple myeloma decreased response AZD4547 Preclinical Actionable In a preclinical study, multiple myeloma cells over expressing FGFR3 G384D had reduced sensitivity to AZD4547 in culture, compared to cells with ligand-independent activation of FGFR3 (PMID: 22869148). 22869148
FGFR3 Y373C FGFR3 over exp multiple myeloma sensitive AZ8010 Preclinical Actionable In a preclinical study, AZ8010 inhibited Fgfr3 signaling, induced cell-cycle arrest, and decreased proliferation of multiple myeloma cells over expressing FGFR3 Y373C in culture (PMID: 22869148). 22869148
FGFR3 G384D FGFR3 over exp multiple myeloma decreased response PD173074 Preclinical Actionable In a preclinical study, multiple myeloma cells over expressing FGFR3 G384D had reduced sensitivity to PD173074 in culture, compared to cells with ligand-independent activation of FGFR3 (PMID: 22869148). 22869148
FGFR2 over exp breast cancer sensitive PD173074 Preclinical Actionable In a preclinical study, PD173074 inhibited proliferation of breast cancer cells over expressing FGFR2 in culture (PMID: 22869148). 22869148
FGFR3 over exp transitional cell carcinoma sensitive AZD4547 Preclinical Actionable In a preclinical study, AZD4547 inhibited proliferation of urothelial cancer cells with over expression of FGFR3 in culture (PMID: 22869148). 22869148
FGFR2 over exp breast cancer sensitive AZD4547 Preclinical Actionable In a preclinical study, AZD4547 inhibited downstream Erk phosphorylation and proliferation of breast cancer cells over expressing FGFR2 in culture (PMID: 22869148). 22869148
ERBB2 amp FGFR2 wild-type stomach cancer resistant AZD4547 Preclinical Actionable In a preclinical study, gastric cancer cells with wild-type FGFR2 and ERBB2 (HER2) amplification were resistant to treatment with AZD4547 in culture (PMID: 22869148). 22869148
FGFR3 K650E FGFR3 over exp HRAS K117E multiple myeloma sensitive PD173074 Preclinical Actionable In a preclinical study, PD173074 inhibited Fgfr3 signaling, induced cell-cycle arrest, and decreased proliferation of multiple myeloma cells harboring HRAS H117E and over expression of FGFR3 K650E in culture (PMID: 22869148). 22869148
FGFR3 - TACC3 urinary bladder cancer sensitive AZ8010 Preclinical Actionable In a preclinical study, AZ12908010 (AZ8010) induced cell cycle arrest and inhibited proliferation of urothelial cancer cell lines that have been demonstrated to harbor FGFR3-TACC3 in culture (PMID: 22869148, PMID: 23175443). 22869148 23175443
FGFR2 over exp breast cancer sensitive AZ8010 Preclinical Actionable In a preclinical study, AZ8010 inhibited downstream Erk phosphorylation and proliferation of breast cancer cells over expressing FGFR2 in culture (PMID: 22869148). 22869148
FGFR3 K650E FGFR3 over exp HRAS K117E myeloid neoplasm sensitive AZ8010 Preclinical Actionable In a preclinical study, AZ8010 inhibited Fgfr3 signaling and decreased proliferation of myeloma cells with HRAS K117E and overexpression of FGFR3 K650E in culture (PMID: 22869148). 22869148
FGFR3 G384D FGFR3 over exp multiple myeloma decreased response AZ8010 Preclinical Actionable In a preclinical study, multiple myeloma cells over expressing FGFR3 G384D had reduced sensitivity to AZ8010 in culture, compared to cells with ligand-independent activation of FGFR3 (PMID: 22869148). 22869148