AZD-4547 exerts potent cytostatic and cytotoxic activities against fibroblast growth factor receptor (FGFR)-expressing colorectal cancer cells

Abstract

Colorectal cancer (CRC) causes significant mortalities worldwide. Fibroblast growth factor (FGF) receptor (FGFR) signaling is frequently dysregulated and/or constitutively activated in CRCs, contributing to cancer carcinogenesis and progression. Here, we studied the activity of AZD-4547, a novel and potent FGFR kinase inhibitor, on CRC cells. AZD-4547 inhibited CRC cell growth in vitro, and its activity correlated with the FGFR-1/2 expression level. AZD-4547 was cytotoxic and pro-apoptotic in FGFR-1/2-expressed CRC cell lines (NCI-H716 and HCT-116), but not in FGFR-1/2 null HT-29 cells. Further, AZD-4547 inhibited cell cycle progression and attenuated the activation of FGFR1-FGFR substrate 2 (FRS-2), ERK/mitogen-activated protein kinase (MAPK), and AKT/mammalian target of rapamycin (AKT/mTOR) signalings in NCI-H716 and HCT-116 cells. In vivo, AZD-4547 oral administration at effective doses inhibited NCI-H716 (high FGFR-1/2 expression) xenograft growth in nude mice. Phosphorylation of FGFR-1, AKT, and ERK1/2 in xenograft specimens was also inhibited by AZD-4547 administration. Thus, our preclinical studies strongly support possible clinical investigations of AZD-4547 for the treatment of CRCs harboring deregulated FGFR signalings.

Fibroblast Growth Factor Receptor 1 (FGFR1) Amplification Detected by Droplet Digital Polymerase Chain Reaction (ddPCR) Is a Prognostic Factor in Colorectal Cancers

“…However, in our present study, the lowest IC50 for PD173074 was observed in the HCT116 cell line, which exhi-bits high FGFR1 expression. Furthermore, BGJ398 and AZD4547 are known to have a strong anti-proliferative effect in CRC cell lines with high FGFR1 expression [14,18]. Therefore, proper selection of a biomarker that can predict the res-ponses to FGFR-targeted therapy is muchneeded.…”

“…The FGFR1 copy number status in these five cell lines was confirmed by ddPCR, while the FGFR1 expression was confirmed by Western blot. The effect of FGFR inhibitor, PD173074, on cell proliferation was determined using the WST-1 assay in SNU-C1, and 3-(4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide (MTT) cell viability assay in the other cell lines [18]. For the WST-1 assay, after the indicated treatment, 20 µL of WST-1 solution was added per well and the cells were incubated for 4 hours at 37°C.…”

FGFR a promising druggable target in cancer: Molecular biology and new drugs

“…AZD4547 has shown promising in vitro results inhibiting cell growth in gastric cancer patient derived cell lines carrying the FGFR2 amplification; it demonstrated good anti-proliferative activity in an endometrial cell line harboring the FGFR2-K310R/N550K mutations. Furthermore, AZD4547 inhibited colorectal cancer cell growth with a high expression of FGFR1-2 with cytotoxic and pro-apoptotic effects (Kwak et al, 2015;Lu et al, 2008d;Yao et al, 2015). A phase II proof of concept study in patients with FGFR1 (HER2 negative breast cancer [BC]/NSCLC) and FGFR2 (gastroesophageal cancer [GC]) amplified tumors demonstrated that AZD4547 has a higher activity in FGFR2 amplified GC (RR 33%) compared to FGFR1 amplified BC (RR 12.5%) (Smyth et al, 2015).…”

Safety, tolerability and pharmacokinetics of the fibroblast growth factor receptor inhibitor AZD4547 in Japanese patients with advanced solid tumours: a Phase I study

“…AZD4547 is a potent, oral, highly selective inhibitor of FGFR1–3 with proven antitumour properties from preclinical studies [11–15], including work in FGFR2-amplified GC xenografts that demonstrated complete and prolonged tumour regression in several AZD4547-treated animals [12]. An initial Phase I study in a Western population indicated that AZD4547 monotherapy has an acceptable safety profile in patients with several tumour types (NCT00979134).…”