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, 145 (5), 1346-1357

Rogaratinib: A Potent and Selective pan-FGFR Inhibitor With Broad Antitumor Activity in FGFR-overexpressing Preclinical Cancer Models

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Rogaratinib: A Potent and Selective pan-FGFR Inhibitor With Broad Antitumor Activity in FGFR-overexpressing Preclinical Cancer Models

Sylvia Grünewald et al. Int J Cancer.

Abstract

Aberrant activation in fibroblast growth factor signaling has been implicated in the development of various cancers, including squamous cell lung cancer, squamous cell head and neck carcinoma, colorectal and bladder cancer. Thus, fibroblast growth factor receptors (FGFRs) present promising targets for novel cancer therapeutics. Here, we evaluated the activity of a novel pan-FGFR inhibitor, rogaratinib, in biochemical, cellular and in vivo efficacy studies in a variety of preclinical cancer models. In vitro kinase activity assays demonstrate that rogaratinib potently and selectively inhibits the activity of FGFRs 1, 2, 3 and 4. In line with this, rogaratinib reduced proliferation in FGFR-addicted cancer cell lines of various cancer types including lung, breast, colon and bladder cancer. FGFR and ERK phosphorylation interruption by rogaratinib treatment in several FGFR-amplified cell lines suggests that the anti-proliferative effects are mediated by FGFR/ERK pathway inhibition. Furthermore, rogaratinib exhibited strong in vivo efficacy in several cell line- and patient-derived xenograft models characterized by FGFR overexpression. The observed efficacy of rogaratinib strongly correlated with FGFR mRNA expression levels. These promising results warrant further development of rogaratinib and clinical trials are currently ongoing (ClinicalTrials.gov Identifiers: NCT01976741, NCT03410693, NCT03473756).

Keywords: cancer; colorectal cancer; fibroblast growth factor receptor; preclinical models; rogaratinib.

Figures

Figure 1
Figure 1
Structure and in vitro activity of rogaratinib. (a) Chemical structure of rogaratinib (BAY 1163877). (b) TREEspot™ interaction map of KINOMEscan™ assay results with 100 nM rogaratinib. (c) Viability of HUVEC cells stimulated with growth factors FGF2 (5 ng/mL) or VEGF‐A (20 ng/mL) in minimal medium after a 72‐h treatment with increasing concentrations of rogaratinib. (d) Correlation of FGFR mRNA levels (sum of Z‐scores for subtypes with Z‐score > 1, derived from CCLE database) and sensitivity (IC50 of inhibition of cell proliferation expressed as LogIC50) to rogaratinib in a panel of cancer cell lines covering various cancer types. Dotted lines indicate IC50 levels.
Figure 2
Figure 2
Effects of rogaratinib treatment on phosphorylation of FGFR and ERK in various cell lines as determined by Western blotting. (a) p‐FGFR4, total FGFR, p(T202/Y204,T185/Y187)‐ERK1/2, and total ERK1/2 expression in MDA‐MB‐453 cells after treatment with 0–1,000 nM rogaratinib. (b) p‐FGFR2, α‐tubulin, p(T202/Y204,T185/Y187)‐ERK1/2, and total ERK1/2 expression in NCI‐H716 cells after treatment with 0 or 100 nM rogaratinib. (c) p(T202/Y204,T185/Y187)‐ERK1/2 and total ERK1/2 expression in UM‐UC‐3, RT‐112, NCI‐H520, NCI‐H1581 and C51 cells after treatment with 0–10,000 nM rogaratinib.
Figure 3
Figure 3
Antitumor activity of rogaratinib in the C51 syngeneic colon cancer model in immunocompetent BALB/c mice and the C51 xenogeneic model in nude rats. (a) Growth curves of C51 colon tumors treated p.o. with vehicle or rogaratinib (25, 50 or 75 mg/kg, QD; or 25 mg/kg BID) in BALB/c mice as measured by tumor volumes (mm3, mean +/− SD) over time. (b) Weights of C51 tumors in mice described in (a) at the end of the study (day 18). (c) Relative volumes (100% equals volume at start of treatment) of C51 tumors described in (a) at the end of the study (day 18) analyzed using RECIST criteria. PD, progressive disease; SD, stable disease; PR, partial response; CR, complete response. (d) Pharmacokinetic profile of rogaratinib in plasma of C51 tumor‐bearing BALB/c mice, shown as unbound concentration over 24 h after the last dose of rogaratinib and simulated exposure levels for the twice daily application of 25 mg/kg. The dotted lines denote the IC50 values of rogaratinib (280 and 430 nM) in C51 cells for inhibition of p‐ERK and proliferation, respectively. (e) Growth curves of C51 tumors in nude rats treated p.o. with vehicle or rogaratinib (10 or 50 mg/kg, QD) as measured by tumor volumes (mm3, mean ± SD) over time. (f) Weight of C51 tumors in rats described in (e) at the end of the study. (g) Relative volumes of C51 tumors described in (e) at the end of the study analyzed using RECIST criteria. PD, progressive disease; SD, stable disease; PR, partial response. Stars in a, b, e and f denote statistical difference compared to vehicle group. *, p < 0.05; **, p < 0.01; ***, p < 0.001; NS, non‐significant. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 4
Figure 4
In vivo antitumor efficacy and mechanism of action of rogaratinib in the human NCI‐H716 colorectal xenograft model in immunocompromised NMRInu/nu mice. (a) Growth curves of human NCI‐H716 colorectal tumors treated p.o. with vehicle or rogaratinib (35, 50 or 65 mg/kg, BID) from days 22 to 38 after tumor inoculation as measured by tumor volumes (mm3, mean ± SD) over time. Stars denote statistical difference compared to vehicle group. **, p < 0.01; ***, p < 0.001. (b) Relative volumes of NCI‐H716 tumors described in (a) on the last treatment day (day 38). PD, progressive disease; SD, stable disease; PR, partial response. (c) Expression of p‐FGFR2, p‐ERK, total ERK and actin in NCI‐H716 tumor tissue after rogaratinib treatment. After a drug‐free observation period of 10 days, mice of the three rogaratinib‐dose groups (35, 50 or 65 mg/kg) in (a) received a single respective dose of rogaratinib or vehicle. Plasma and tumors were collected 1, 2, 5 or 24 h after treatment for PK/PD analysis and phosphorylation of FGFR2 and ERK1/2 was determined by Western blotting. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 5
Figure 5
In vivo antitumor efficacy of rogaratinib in the DMS‐114 lung cancer xenograft model. (a) Growth curves of DMS‐114 lung tumors treated with vehicle, rogaratinib (50 mg/kg, p.o., BID), docetaxel (30 mg/kg, i.v., Q7D), combination of rogaratinib (50 mg/kg, BID)/docetaxel (30 mg/kg, Q7D), combination of carboplatin (80 mg/kg, i.p., Q7D)/paclitaxel (24 mg/kg, Q7D) or combination of carboplatin (80 mg/kg, Q7D)/paclitaxel (24 mg/kg, i.p., Q7D)/rogaratinib (50 mg/kg, BID), as measured by tumor volumes (mm3, mean ± SD) over time. (b) Weights of DMS‐114 tumors described in (a) at the end of the study. (c) Relative volumes of DMS‐114 tumors described in (a) at the end of the study. PD, progressive disease; SD, stable disease; PR, partial response; CR, complete response. (d) Body weights of mice described in (a) relative to body weights at treatment start. Stars denote statistical difference compared to vehicle group. **, p < 0.01; ***, p < 0.001.
Figure 6
Figure 6
In vivo antitumor efficacy of rogaratinib in the patient‐derived LU299 lung cancer xenograft model. (a) Growth curves of LU299 lung tumors treated with vehicle, rogaratinib (50 mg/kg, BID), docetaxel (15 mg/kg, i.v., Q7D), or combination of rogaratinib and docetaxel for 33 days followed by a drug‐free observation period of 53 days, as measured by tumor volumes (mm3, mean ± SD) over time. Stars denote statistical difference compared to vehicle group. *, p < 0.05; ***, p < 0.01. (b) Relative volumes of tumors described in (a) at the last treatment day (day 54 after tumor inoculation). PD, progressive disease; SD, stable disease; PR, partial response; CR, complete response. (c) Relative body weights of LU299 mice described in (a). Body weight loss in docetaxel groups recovered after dosing break at day 37. (d) Growth curves of single mice of LU299 lung tumors treated as noted above (a).

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References

    1. Katoh M. Therapeutics targeting FGF signaling network in human diseases. Trends Pharmacol Sci 2016;37:1081–96. - PubMed
    1. Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 2010;10:116–29. - PubMed
    1. Helsten T, Elkin S, Arthur E, et al. The FGFR landscape in cancer: analysis of 4,853 tumors by next‐generation sequencing. Clin Cancer Res 2016;22:259–67. - PubMed
    1. Cihoric N, Savic S, Schneider S, et al. Prognostic role of FGFR1 amplification in early‐stage non‐small cell lung cancer. Br J Cancer 2014;110:2914–22. - PMC - PubMed
    1. Heist RS, Mino‐Kenudson M, Sequist LV, et al. FGFR1 amplification in squamous cell carcinoma of the lung. J Thorac Oncol 2012;7:1775–80. - PMC - PubMed

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