Abstract IA29: PI3′ -kinase inhibition forestalls the onset of MEK1/2 inhibitor resistance in BRAFV600E/PTENNull melanoma

Abstract

Abstract Phosphatidylinositide 3′ (PI3′)-lipid signaling promotes the growth of BRAF-mutated melanomas initiated by expression of oncogenic BRAFV600E. Elevation of PI3′-lipid signaling commonly occurs via silencing of the PTEN tumor suppressor, which encodes a PI3′-lipid phosphatase. However mutational activation of PIK3CA, encoding the p110α catalytic subunit of PI3′-kinase (PI3K), or alterations in the PI3′-lipid effectors AKT1-3 have also been observed, albeit infrequently. To characterize the PI3K catalytic isoform dependency of BRAF-mutated melanoma, we utilized a panel of pharmacological isoform-selective PI3K inhibitors in conjunction with melanoma-derived cell lines and genetically engineered mouse (GEM) models of BRAF-mutated melanoma. While BRAFV600E/PIK3CAH1047R mutated melanoma was sensitive to p110α selective blockade, inhibition of BRAFV600E/PTENNull melanoma cell proliferation required combined blockade of p110α, p110δ and p110γ isoforms, and was insensitive to p110β blockade. In GEM models of BRAF-mutated melanoma, PI3K pathway inhibition elicited largely cytostatic effects, and significantly potentiated melanoma regression in response to BRAFV600E pathway-targeted inhibition. Interestingly, an inhibitor of p110α, δ and γ forestalled the onset of MEK inhibitor resistance in a GEM model of BRAFV600E/PTENNull melanoma. Thus, although single agent PI3K inhibition failed to elicit dramatic regression of BRAFV600E expressing melanomas, PI3K inhibitors may be useful in extending the duration of response to BRAFV600E pathway-targeted therapy. Citation Format: Marian M. Deuker, Victoria Marsh-Durban, Wayne A. Phillips, Jillian M. Silva, Martin McMahon. PI3′ -kinase inhibition forestalls the onset of MEK1/2 inhibitor resistance in BRAFV600E/PTENNull melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr IA29.