1. Fig. 6. FGFR1 and CCND1 amplification–mediated resistance to estrogen deprivation is therapeutically actionable.
FGFR1 and CCND1 amplification–mediated resistance to estrogen deprivation is therapeutically actionable. (A) FGFR1 and CCND1 coamplified CAMA1 breast cancer cells were seeded in estrogen-free medium supplemented with FGF3/19 (100 ng/ml) and treated with 500 nM of the CDK4/6 inhibitor, palbociclib (Palbo), and/or 1 μM of the FGFR1 inhibitor, lucitanib (Luc). When the untreated control cells reached 50 to 70% confluence (day 12), the cells were fixed and stained with crystal violet, and two-dimensional (2D) growth was quantified. The combination of palbociclib + lucitanib was sufficient to overcome resistance to estrogen withdrawal better than either single agent. ns, not significant. Further highlighting this effect, (B) presents the CI values calculated based on the average of the fold change in 2D growth with increasing combination doses of lucitanib (0 to 1000 nM) and palbociclib (0 to 500 nM) relative to untreated controls from three independent experiments. CI < 1 represents synergism, CI = 1 represents an additive effect, and CI > 1 represents antagonism. (C) S phase analysis of CAMA1 cells treated with FGF3/19 (100 ng/ml), ±1 μM lucitanib, and ±500 nM palbociclib reveals that treatment with palbociclib or the combination of lucitanib + palbociclib can overcome FGF-induced persistence of CAMA1 cells under estrogen-deprived conditions. Individual plots for each treatment condition can be found in fig. S7A. (D) Finally, immunoblot analysis of CAMA1 whole-cell lysates shows that only combined inhibition of FGFR1 and CDK4/6 can simultaneously decrease extracellular signal–regulated kinase 1/2 (ERK1/2) and Rb phosphorylation. P values represent results of two-way Student’s t test. Lucitanib = 1 μM and palbociclib = 500 nM. Comb, combination of lucitanib and palbociclib.
Jennifer M. Giltnane et al., Sci Transl Med 2017;9:eaai7993
Published by AAAS