Melanoma and immunotherapy bridge 2015

Abstract

The PI3K/AKT/mTOR signaling pathway has been implicated in multiple cancers, and as a regulator of many key oncogenic processes. Our studies implicate a role for this pathway in resistance to both targeted and immune therapies for melanoma. Materials and methods: Melanoma cell lines and clinical specimens were utilized to study the significance and functional consequences of the PI3K/AKT/mTOR pathway. Analyses of clinical specimens were performed under institution review board-approved protocols. Results: Pilot whole genome expression profiling and synthetic lethality screens implicated oxidative phosphorylation (OxPhos) in resistance to BRAF and MEK inhibitors in BRAF-mutant human melanoma cell lines. Characterization of panels of human cell lines with de novo or acquired resistance to MAPK pathway inhibitors demonstrated that ~50 % of the cell lines exhibited a high OxPhos phenotype. The presence of high OxPhos correlated with increased expression of PGC1-alpha and with sensitivity to combined inhibition of the MAPK pathway and mTORC1/2. mTORC1/2 inhibition caused cytoplasmic sequestration of MITF and subsequent decreased expression of MITF-regulated genes, including PGC1-alpha. In vitro testing demonstrated that a direct OxPhos inhibitor similarly achieved growth inhibition and apoptosis in some human melanoma cell lines with high OxPhos. Further, the OxPhos inhibitor abrogated the growth of inhibitor-resistant BRAF mutant human melanoma cell lines in vivo. Activation of the PI3K/AKT/mTOR pathway by loss of PTEN was also shown to promote resistance to T cell mediated cell killing in vitro and in vivo. Loss of PTEN correlated with decreased CD8 cell infiltrates in clinical specimens and increased expression of immunosuppressive cytokines. While pan-PI3K inhibitors inhibited immune cell viability and function, isoform-selective inhibitors did not significantly affect immune function and they produced synergy with immunotherapy. Conclusions: The PI3K/AKT/mTOR signaling pathway is an important regulator of key cellular processes in melanoma, and should be considered as a candidate combinatorial partner for both targeted and immune therapies.