Abstract A09: Cooperation of the MAPK and PI3K&gt;AKT&gt;mTORC1 signaling pathways is required for PIK3CA mutant melanoma maintenance
Authors: Silva Jillian M. , Deuker Marian M. , Joseph Wayne R. , Baguley Bruce C. , McMahon Martin 
Published: October 2015

Activating mutations in BRAF and NRAS are the most common genetic alterations that occur in melanoma resulting in the constitutive activation of the ERK1/2 MAP kinase (MAPK) pathway. However, oncogenic transformation of BRAF or NRAS expressing melanocytes often require the cooperation of additional genetic events, in which aberrations in the PI3K&gt;AKT signaling pathway are consistently found in conjunction with these activating mutations. Although oncogenic NRAS is also thought to activate the PI3K pathway, activating mutations in the p110 alpha catalytic subunit of PI3K (PIK3CA) are detected at a low frequency in both BRAF and NRAS-mutated melanomas. Since the mechanism(s) underlying this cooperation still remains elusive, we explored the contribution of alpha-specific PI3K signaling to the cooperation between the MAPK and PI3K&gt;AKT pathways using pathway-targeted inhibitors and human melanoma-derived cell lines that contain a PIK3CAH1047R and either a BRAFV600E or NRASQ61H mutation. Inhibition of MEK or either class I or alpha-specific PI3K&gt;AKT&gt;mTORC1 elicited antiproliferative effects against NRASQ61H, PIK3CAH1047R mutant melanoma cells, whereas the combinatorial inhibition of these signaling pathways was significantly more potent. Even though blockade of class I PI3K or mTORC1 inhibited BRAFV600E, PIK3CAH1047R-mutated melanoma proliferation, these cells were insensitive to single-agent inhibition of BRAFV600E&gt;MEK or alpha-specific PI3K&gt;AKT. However, only the combined inhibition of MEK and alpha-specific PI3K&gt;AKT led to a significant decrease in proliferation. Examination of signaling downstream of BRAFV600E or NRASQ61H and PI3K&gt;AKT revealed that these pathways cooperated to regulate the phosphorylation of the cap-dependent translation regulators, p70S6K, ribosomal protein S6, and 4E-BP1 through mTORC1-dependent effects. While the combined inhibition of MEK and either class I or alpha-specific PI3K signaling resulted in a significant regression of NRASQ61H, PIK3CAH1047R mutant xenograft tumors, the combinatorial inhibition of MEK and class I PI3K showed a greater tumor reduction than the inhibition of MEK and alpha-specific PI3K. Taken together, these data suggest that a PIK3CA mutation does not entirely predict for sensitivity to alpha-specific PI3K inhibition. Furthermore, this study demonstrates that MAPK and PI3K&gt;AKT&gt;mTORC1 signaling cooperates for melanoma maintenance and provides a biochemical basis for combined pathway-targeted therapy for PIK3CA and BRAF or NRAS-mutated melanoma.

Citation Format: Jillian M. Silva, Marian M. Deuker, Wayne R. Joseph, Bruce C. Baguley, Martin McMahon. Cooperation of the MAPK and PI3K&gt;AKT&gt;mTORC1 signaling pathways is required for PIK3CA mutant melanoma maintenance. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A09.