Differential AKT dependency displayed by mouse models of BRAFV600E-initiated melanoma
Victoria Marsh Durban, … , Wayne Phillips, Martin McMahon
Victoria Marsh Durban, … , Wayne Phillips, Martin McMahon
Published November 8, 2013
Citation Information: J Clin Invest. 2013;123(12):5104-5118. https://doi.org/10.1172/JCI69619.
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Research Article Oncology

Differential AKT dependency displayed by mouse models of BRAFV600E-initiated melanoma

Abstract

Malignant melanoma is frequently driven by mutational activation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) accompanied by silencing of the phosphatase and tensin homology (PTEN) tumor suppressor. Despite the implied importance of PI3K signaling in PTENNull melanomas, mutational activation of the gene encoding the catalytic subunit of PI3Kα (PIK3CA), is rarely detected. Since PTEN has both PI3-lipid phosphatase–dependent and –independent tumor suppressor activities, we investigated the contribution of PI3K signaling to BRAFV600E-induced melanomagenesis using mouse models, cultured melanoma cells, and PI3K pathway–targeted inhibitors. These experiments revealed that mutationally activated PIK3CAH1047R cooperates with BRAFV600E for melanomagenesis in mice. Moreover, pharmacological inhibition of PI3Ks prevented growth of BRAFV600E/PTENNull melanomas in vivo and in tissue culture. Combined inhibition of BRAFV600E and PI3K had more potent effects on the regression of established BRAFV600E/PTENNull melanomas and cultured melanoma cells than individual blockade of either pathway. Surprisingly, growth of BRAFV600E/PIK3CAH1047R melanomas was dependent on the protein kinase AKT; however, AKT inhibition had no effect on growth of BRAFV600E/PTENNull melanomas. These data indicate that PTEN silencing contributes a PI3K-dependent, but AKT-independent, function in melanomagenesis. Our findings enhance our knowledge of how BRAFV600E and PI3K signaling cooperate in melanomagenesis and provide preclinical validation for combined pathway–targeted inhibition of PI3K and BRAFV600E in the therapeutic management of BRAFV600E/PTENNull melanomas.

Authors

Victoria Marsh Durban, Marian M. Deuker, Marcus W. Bosenberg, Wayne Phillips, Martin McMahon

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Figure 6

PI3K inhibition has modest antimelanoma therapeutic activity in vivo, but promotes regression of established tumors in response to BRAFV600E inhibition with LGX-818.

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PI3K inhibition has modest antimelanoma therapeutic activity in vivo, bu...
(A) Growth of BRAFV600E/PIK3CAH1047R melanomas in the absence (solid line) or presence of PI3K inhibitor BKM-120 (dashed line) was measured (displayed as percentage change in tumor volume ± SD). (B) Tumor lysates from vehicle- or BKM-120–treated BRAFV600E/PTENNull or BRAFV600E/PIK3CAH1047R melanomas at 4–16 hours after dosing were probed with antisera against the various indicated proteins. (C) Established BRAFV600E/PTENNull melanomas (∼45–60 days after initiation), were treated with vehicle (n = 5, solid line), BKM-120 (n = 6, dotted line), LGX-818 (n = 6, dashed line), or combined LGX-818/BKM-120 (n = 6, dot-dashed line). Tumors were measured weekly (displayed as percentage change in tumor volume ± SD). After 50 days, drug treatment ceased (indicated by arrow). Tumor measurement continued in mice that had received LGX-818 single-agent or combination therapy. *P < 0.01; **P < 0.05. (D) Best overall response of mice treated with vehicle (white bars), BKM-120 (light gray bars), LGX-818 (dark gray bars), or combination treatment (black bars). Mice with progressive disease over the course of the study were arbitrarily set to 100% change in tumor size. Mice bearing lesions that became unmeasurable during the course of treatment were determined to have a –100% change in tumor size. (E) Tumor lysates from BRAFV600E/PTENNull melanomas treated with vehicle, single-agent LGX-818, single-agent BKM-120, or LGX-818 plus BKM-120 in combination as indicated were probed with various antisera as indicated.