Figure 6: Oxidative phosphorylation is functionally significant for melanoma brain metastasis pathogenesis.

(A) Pimonidazole staining of ICr A375-R1 xenografts treated with either IACS-010759 (5 mg/kg PO once daily) or 0.5% methylcellulose vehicle control. Y-axis indicates percentage of total tumor positivity. Average values and S.D. of three biological replicates per condition are displayed. Significance determined via two-sided Student’s t-test. (B) Representative pimonidazole staining analysis results of ICr A375-R1 xenografts treated for 1 week with IACS-010759 (5 mg/kg PO once daily) or vehicle. (C) Kaplan-Meier OS analysis of mice bearing ICr A375-R1 xenografts and treated with either IACS-010759 (5 mg/kg PO once daily) or vehicle. Hazard ratio generated via Mantel-Haenszel test. Significance determined via log-rank test. (D) Kaplan-Meier OS analysis of mice bearing ICr SKMEL5 xenografts and treated with either IACS-010759 (5 mg/kg PO once daily) or vehicle. Treatments ended 42 days after randomization. Hazard ratio generated via Mantel-Haenszel test and significance determined via log-rank test. (E) Comparison of Braf^V600E;Cdkn2a^−/−;Pten^−/−;myrAkt1 primary tumor growth rates in mice treated with IACS-010759 (7.5 mg/kg PO once daily) or vehicle upon initial detection of palpable tumor. Rated-based T/C metric (34) was used to reflect primary tumor growth rates. Significance determined via two-sided Student’s t-test. (F) Incidence of brain and lung metastases in mice with Braf^V600E;Cdkn2a^−/−;Pten^−/−;myrAkt1 primary tumors treated with IACS-010759 (7.5 mg/kg PO once daily) or vehicle. Systemic treatment was started upon initial detection of palpable primary tumor. Y-axis indicates tumor incidence, and x-axis indicates metastatic site. Significance determined via Fisher’s exact test.