Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Oncogene	32	25	2013 Jun 20	3059-70	Oncogene

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	6	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AZ6089		AZ12576089	FGFR Inhibitor (Pan) 26	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 28 FGFR2 Inhibitor 23 FGFR3 Inhibitor 19	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 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 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 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
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
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 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
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
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
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	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
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	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
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 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	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	multiple myeloma	sensitive	PD173074	Preclinical - Cell culture	Actionable	In a preclinical study, PD173074 inhibited Fgfr3 signaling, induced cell cycle arrest, and decreased proliferation of multiple myeloma cells harboring HRAS K117E and overexpression of FGFR3 K650E in culture (PMID: 22869148).	22869148