Effect of Tasurgratinib as an Orally Available FGFR1-3 Inhibitor on Resistance to a CDK4/6 Inhibitor and Endocrine Therapy in ER+/HER2- Breast Cancer Preclinical Models

Abstract

Background: Fibroblast growth factor (FGF) signaling plays a crucial role in several cellular functions in cancer cells. Tasurgratinib, formerly known as E7090, is an orally available FGF receptor (FGFR)1-3 selective inhibitor. Here, we present the effects of tasurgratinib on the resistance to CDK4/6 inhibitors and endocrine therapy (ET) in a preclinical model.

Methods: Estrogen receptor (ER)⁺ breast cancer (BC) patient-derived xenograft (PDX) models harboring ESR1 wild-type or ESR1 mutation were used as animal models. An in vitro cell proliferation assay of ER⁺ BC cell lines treated with fulvestrant or palbociclib + fulvestrant was conducted in the presence of FGF2 and FGF10, with or without tasurgratinib.

Results: Among five ER⁺ BC PDX models, OD-BRE-0438 and OD-BRE-0704 showed higher sensitivities to tasurgratinib with prior palbociclib + fulvestrant than without it. In these models, palbociclib + fulvestrant treatment upregulated the expression of several FGF ligand mRNAs. In vitro, FGF2 and FGF10 decreased the sensitivity to both fulvestrant and palbociclib + fulvestrant, which was restored by co-treatment with tasurgratinib. Consistently, fulvestrant + tasurgratinib and elacestrant + tasurgratinib showed antitumor activity in ER⁺ BC PDX models harboring ESR1 wild-type and ESR1 mutation, respectively. In these models, fulvestrant or elacestrant upregulated the expression of several FGF ligand mRNAs.

Conclusions: FGF signaling plays a role in resistance to CDK4/6 inhibitors and ET in ER⁺ BC. Tasurgratinib has the potential to exhibit significant antitumor activity in combination with ET against ER⁺ BC via FGF signaling inhibition. These findings indicate the therapeutic potential of tasurgratinib in treating ER⁺ BC.

Keywords: CDK4/6 inhibitor; FGFR; breast cancer; endocrine therapy; tasurgratinib.

Figure 1

Antitumor activity and gene expression alterations of FGF/FGFR with palbociclib + fulvestrant in five ER⁺ breast cancer PDX models (OD-BRE-0438, OD-BRE-0704, OD-BRE-0450, OD-BRE-0188, IM-BRE-556). (a) Relative tumor volume (upper) and relative body weight (lower) after treatment with palbociclib (100 mg/kg, once daily [Q1D] × 21) in combination with fulvestrant (5 mg/mouse, once a week [Q7D] × 3). Data show the mean (no treatment groups: n = 2 per group) or the mean ± SEM (palbociclib + fulvestrant treatment groups: n = 3 per group). (b) Alterations of human mRNA expression in tumors collected on the day following the treatment with palbociclib (100 mg/kg, Q1D × 14) in combination with fulvestrant (250 mg/kg, Q7D × 2). Data show the geometric mean (OD-BRE-0450 and OD-BRE-0188: n = 2 per group) or the geometric mean ± geometric SD (OD-BRE-0438: n = 6 per group, OD-BRE-0704 and IM-BRE-556: n = 3 per group). The expressions of FGF1 in OD-BRE-0450 and IM-BRE-556, FGF7 in IM-BRE-556, FGF8 in OD-BRE-0704, and FGF10 in OD-BRE-0450 and OD-BRE-0188 were not detected in both baseline and post-treatment. * p < 0.05, ** p < 0.01 versus the no treatment group (unpaired t-test) in the OD-BRE-0438 and IM-BRE-556 models in which mouse numbers were more than two in both no treatment groups and treated groups. Values of Ct and delta Ct, p-values in unpaired t-test, and ratio to no treatment are shown in File S2. mPFS: median progression-free survival; ns: not significant.

Figure 2

Antitumor activity of tasurgratinib with or without prior palbociclib + fulvestrant treatment in five ER⁺ breast cancer PDX models (OD-BRE-0438, OD-BRE-0704, OD-BRE-0450, OD-BRE-0188, and IM-BRE-556). Relative tumor volume (upper) and relative body weight (lower) after the treatment with tasurgratinib (25 mg/kg, once daily [Q1D] × 14 or Q1D × 21) with no prior treatment (a) or with prior treatment with palbociclib (100 mg/kg, Q1D × 14) in combination with fulvestrant (250 mg/kg, once a week × 2) (b). * p < 0.05, **** p < 0.0001 versus the no treatment group (repeated measures analysis of variance). (c) dT/C (% of control) for tumor growth in models of OD-BRE-0438, OD-BRE-0704, and OD-BRE-0450, and T/C (% of control) in the OD-BRE-0188 and IM-BRE-556 models. * p < 0.05, *** p < 0.001 versus the no treatment group (unpaired t test), † p < 0.05, †††† p < 0.0001 the no-prior-treatment cohort versus with-prior-treatment cohort (unpaired t test). Values of dT/C (% of control) for tumor growth in models of OD-BRE-0438, OD-BRE-0704, and OD-BRE-0450, and T/C (% of control) values in the OD-BRE-0188 and IM-BRE-556 models are shown in File S3. The numbers of mice used in each group were indicated within the figure. Data show the mean (n < 3 per group) or the mean ± SEM (n ≥ 3 per group). ns: not significant, NT: no treatment, Tasur: tasurgratinib.

Figure 3

Anti-proliferative activity of tasurgratinib, fulvestrant, or palbociclib + fulvestrant against ER⁺ breast cancer cell lines with FGF stimulation in vitro. (a) In vitro study to analyze the effect of tasurgratinib on cell growth in the presence of 25 ng/mL FGF2 and 100 ng/mL FGF10 in ER⁺ breast cancer cell lines, MCF7, ZR-75-1, and HCC1428. (b,c) In vitro study to analyze the effect of FGF stimulation using 25 ng/mL FGF2 and 100 ng/mL FGF10 with or without tasurgratinib on cell growth inhibitory activities of fulvestrant (b) or palbociclib + fulvestrant (100 nmol/L) combination (c) in ER⁺ breast cancer cell lines, MCF7, ZR-75-1, and HCC1428. Data show the ratio to control (without tasurgratinib [a], without fulvestrant [b], or without palbociclib + fulvestrant [c] in each culture condition; mean ± SD; n = 3 per group). Values of ratio to control are shown in File S4. CI: confidence interval, Fulv: fulvestrant, IC₅₀: 50% inhibitory concentration, ND: not determined, NE: not estimable, Palb: palbociclib, Tasur: tasurgratinib.

Figure 4

Human mRNA expression in tumors collected the day after the two-week treatment. (a) Treatment with fulvestrant (250 mg/kg, once a week × 2) in the OD-BRE-0438 model. (b) Treatment with elacestrant (30 mg/kg, once daily [Q1D] × 15) in the ST2056 model. (c) Treatment with elacestrant (30 mg/kg, Q1D × 15) in the ST2535 model. Data show the geometric mean ± geometric SD (n = 5 per group for OD-BRE-0438, n = 6 per group for ST2056 and ST2535). ** p < 0.01, **** p < 0.0001 versus the no treatment group (unpaired t-test). Values of Ct and delta Ct, p-values in unpaired t-test, and ratio to no treatment are shown in File S5. Elac: elacestrant, Fulv: fulvestrant, NT: no treatment.

Figure 5

Combination activity of tasurgratinib on fulvestrant or elacestrant in ER⁺ breast cancer PDX models. Relative tumor volume (upper) and relative body weight (lower) are shown. (a) Treatment with tasurgratinib (25 mg/kg, once daily [Q1D] × 14) or fulvestrant (250 mg/kg, once a week [Q7D] × 2) or both in the OD-BRE-0438 model. (b) Treatment with tasurgratinib (25 mg/kg, Q1D × 21) or elacestrant (30 mg/kg, Q1D × 21) or both in the ST2056 model. (c) Treatment with tasurgratinib (25 mg/kg, Q1D × 21) or elacestrant (30 mg/kg, Q1D × 21) or both in the ST2535 model. Data show the mean ± SEM (n = 5 per group for the OD-BRE-0438 model, n = 6 per group for the ST2056 model, and n = 6 per group [no treatment group and tasurgratinib group] or n = 5 per group [elacestrant group and combination group] for the ST2535 models). * p < 0.05, *** p < 0.001 versus the no treatment group, † p < 0.05, †† p < 0.01 versus the combination group (one-way analysis of variance [ANOVA] followed by Dunnett’s multiple comparison test by using relative tumor volumes on Day 15 in the OD-BRE-0438 model. Repeated measures ANOVA followed by Dunnett’s multiple comparison test in the ST2056 and ST2535 models). Elac: elacestrant, Fulv: fulvestrant, Tasur: tasurgratinib.