Figure 1. Short-Term Antiangiogenic Treatment Withdrawal following Resistance Accelerates In Vivo Tumor Growth and Metastasis.

(A) Schematic of ortho-surgical model used to generate VEGFR TKI treatment-resistant spontaneous Met cells to study the impact of ST-W and LT-W periods (24–48 hr and 2–6 months, respectively).

(B) Representative example of mouse breast 4T1^SuR cell generation with PT growth/resection and post-surgical Met shown in BALB/c mice by bioluminescence imaging (BLI).

(C–E) Orthotopic tumor growth responses following repeated SuR cell Met variant selection and drug exposure during re-implantation into treatment-naive mice. (C) Human breast LM2–4^SuR cells (SCID; n = 5–12 mice, 2 cycles), (D) human melanoma MeWo^SuR (nu/nu; n = 4, 2 cycles), and (E) mouse breast 4T1^SuR (BALB/c; n = 3–5, 1 cycle).

(F–I) In vivo-derived (and in vitro-maintained) SuR cells implanted orthotopically to monitor PT growth progression (left), final tumor weight at resection (left, inset), and post-surgical survival (right) after ST-W. (F) LM2–4^SuR (SCID; n = 4), (G) MeWo^SuR (SCID; n = 4–5), (H) 4T1^SuR (BALB/c; n = 5), and (I) SN12-PM6-N^SuR (SCID; n = 6–11; only final kidney weight and survival shown).

Veh, vehicle; Su, sunitinib; Ax, axitinib; P, parental; SuR, sunitinib-resistant; AxR, axitinib-resistant; ST-W, short-term withdrawal; LT-W, long-term withdrawal; PT, primary tumor; Tx, treatment; Met, metastasis; +/−, with/without treatment. Su (60 mg/kg/day); Ax (100 mg/kg/day). PT burden was assessed by caliber measurement and/or excised tumor or kidney weight. Overall Survival was based on Kaplan-Meier. Quantitative data are shown as mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001, compared to animals implanted with parental cell lines or untreated resistant cells.

See also Figure S1.