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 BRAF. 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-a, 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 BRAF/PTEN as well as BRAF/PIK3CA 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 BRAF/PIK3CA melanoma was sensitive to p110a-selective inhibition, inhibition of BRAF/PTEN melanoma cell proliferation required combined blockade of p110a (PIK3CA), p110d (PIK3CD) and p110g (PIK3CG). Moreover, in GEM models of BRAF/PIK3CA or BRAF/PTEN 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 p110b-sparing PI3K inhibitor, forestalled the onset of MEK inhibitor (GDC-973, cobimetinib) resistant disease in the BRAF/PTEN GEM model of melanoma. Together, these data suggest that PIK3CAmutational status may be used to select for melanoma patients that will respond to a p110a-selective inhibitor. By contrast, PTEN melanoma patients will require a p110b-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 BRAF pathway-targeted therapy.

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