A. MCF7 tumor growth rate in NOD/SCID mice implanted with beeswax E2 pellets, commercial 0.72 mg/60 days E2 pellets (Innovative Research of America) and control mice. Both, 0.72 mg/60 days E2 and beeswax E2 pellets equally supported estrogen dependent tumor growth. In contrast, control mice not supplemented with E2 pellets failed to grow tumors. B. Quantification of E2 plasma levels 10 days post implantation of E2 pellets in NOD/SCID mice. The beeswax pellets yielded mean E2 plasma levels of 84 pg/ml with very little variation, which are comparable plasma estrogen levels released from commercially available E2 pellets.
ARTICLE ABSTRACT
Purpose: Recent studies have demonstrated that short-form Ron (sfRon) kinase drives breast tumor progression and metastasis through robust activation of the PI3K pathway. We reasoned that upfront, concurrent inhibition of sfRon and PI3K might enhance the antitumor effects of Ron kinase inhibitor therapy while also preventing potential therapeutic resistance to tyrosine kinase inhibitors (TKI).Experimental Design: We used patient-derived breast tumor xenografts (PDX) as high-fidelity preclinical models to determine the efficacy of single-agent or dual Ron/PI3K inhibition. We tested the Ron kinase inhibitor ASLAN002 with and without coadministration of the PI3K inhibitor NVP-BKM120 in hormone receptor–positive [estrogen receptor (ER)+/progesterone receptor (PR)+] breast PDXs with and without PIK3CA gene mutation.Results: Breast PDX tumors harboring wild-type PIK3CA showed a robust response to ASLAN002 as a single agent. In contrast, PDX tumors harboring mutated PIK3CA demonstrated partial resistance to ASLAN002, which was overcome with addition of NVP-BKM120 to the treatment regimen. We further demonstrated that concurrent inhibition of sfRon and PI3K in breast PDX tumors with wild-type PIK3CA provided durable tumor stasis after therapy cessation, whereas discontinuation of either monotherapy facilitated tumor recurrence.Conclusions: Our work provides preclinical rationale for targeting sfRon in patients with breast cancer, with the important stipulation that tumors harboring PIK3CA mutations may be partially resistant to Ron inhibitor therapy. Our data also indicate that tumors with wild-type PIK3CA are most effectively treated with an upfront combination of Ron and PI3K inhibitors for the most durable response. Clin Cancer Res; 21(24); 5588–600. ©2015 AACR.
