Abstract B11: PI3-kinase inhibition forestalls the development of drug resistance in BRAFV600E/PTENNull melanoma

Abstract

Abstract The phosphatidylinositol 3′-kinase (PI3K) signaling pathway is frequently dysregulated in BRAF mutated melanomas and serves to promote the growth of tumors initiated by expression of BRAFV600E. The most prevalent mechanism of PI3K pathway activation occurs via silencing expression of the phosphatase and tensin homolog (PTEN) tumor suppressor, but mutational activation of PIK3CA, encoding the 110kDa catalytic subunit of PI3□-kinase-α, has also been observed at low frequency. However, the PI3K catalytic isoform dependence of BRAF mutated melanoma remains poorly understood, as does the differential isoform dependence imbued by discrete nodes of PI3K pathway dysregulation. To characterize the PI3K isoform dependence of BRAFV600E/PTENNull as well as BRAFV600E/PIK3CAH1047R melanoma, we administered a panel of isoform-selective PI3K inhibitors to cultured melanoma cells and to genetically engineered mouse (GEM) models of melanoma of both genotypes. These studies revealed that, while BRAFV600E/PIK3CAH1047R melanoma was sensitive to p110α-selective inhibition, inhibition of BRAFV600E/PTENNull melanoma cell proliferation required combined blockade of p110α (PIK3CA), p110δ (PIK3CD) and p110γ (PIK3CG). Moreover, in GEM models of BRAFV600E/PIK3CAH1047R or BRAFV600E/PTENNull melanoma, isoform-selective PI3K inhibition elicited only a cytostatic effect as monotherapy, but enhanced melanoma regression in response to BRAFV600E→MEK→ ERK pathway-targeted inhibition. Most interestingly, treatment with GDC0032, a p110β-sparing PI3K inhibitor, forestalled the onset of MEK inhibitor (GDC-973, cobimetinib) resistant disease in the BRAFV600E/PTENNull GEM model of melanoma. Together, these data suggest that PIK3CA mutational status may be used to select for melanoma patients that will respond to a p110α-selective inhibitor. By contrast, PTENNull melanoma patients will require a p110β sparing pan-class I PI3K inhibitor. Moreover, although monotherapy PI3K inhibition did not elicit dramatic tumor regression, blockade of this pathway may be a useful strategy to extend the duration of response to BRAFV600E pathway-targeted therapy. Citation Format: Marian M. Deuker, Victoria Marsh Durban, Wayne Phillips, Martin McMahon. PI3-kinase inhibition forestalls the development of drug resistance in BRAFV600E/PTENNull melanoma. [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 B11.