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Oncogenic PI3K mutations lead to NF-?B-dependent cytokine expression following growth factor deprivation.

ABSTRACT: The phosphoinositide 3-kinase (PI3K) pathway is one of the most commonly misregulated signaling pathways in human cancers, but its impact on the tumor microenvironment has not been considered as deeply as its autonomous impact on tumor cells. In this study, we show that NF-?B is activated by the two most common PI3K mutations, PIK3CA E545K and H1047R. We found that markers of NF-?B are most strongly upregulated under conditions of growth factor deprivation. Gene expression analysis conducted on cells deprived of growth factors identified the repertoire of genes altered by oncogenic PI3K mutations following growth factor deprivation. This gene set most closely correlated with gene signatures from claudin-low and basal-like breast tumors, subtypes frequently exhibiting constitutive PI3K/Akt activity. An NF-?B-dependent subset of genes driven by oncogenic PI3K mutations was also identified that encoded primarily secreted proteins, suggesting a paracrine role for this gene set. Interestingly, while NF-?B activated by oncogenes such as Ras and EGF receptor leads to cell-autonomous effects, abrogating NF-?B in PI3K-transformed cells did not decrease proliferation or induce apoptosis. However, conditioned media from PI3K mutant-expressing cells led to increased STAT3 activation in recipient THP-1 monocytes or normal epithelial cells in a NF-?B and interleukin-6-dependent manner. Together, our findings describe a PI3K-driven, NF-?B-dependent transcriptional profile that may play a critical role in promoting a microenvironment amenable to tumor progression. These data also indicate that NF-?B plays diverse roles downstream from different oncogenic signaling pathways.

SUBMITTER: Hutti JE

PROVIDER: S-EPMC3541677 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Oncogenic PI3K mutations lead to NF-κB-dependent cytokine expression following growth factor deprivation.

Hutti Jessica E JE Pfefferle Adam D AD Russell Sean C SC Sircar Mayukh M Perou Charles M CM Baldwin Albert S AS

Cancer research 20120502 13

The phosphoinositide 3-kinase (PI3K) pathway is one of the most commonly misregulated signaling pathways in human cancers, but its impact on the tumor microenvironment has not been considered as deeply as its autonomous impact on tumor cells. In this study, we show that NF-κB is activated by the two most common PI3K mutations, PIK3CA E545K and H1047R. We found that markers of NF-κB are most strongly upregulated under conditions of growth factor deprivation. Gene expression analysis conducted on ...[more]

PMID: 22552288

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Project description:ObjectiveAberrant expression of HER2/neu and PIK3CA gene products secondary to amplification/mutations are common in high-grade-serous-endometrial (USC) and ovarian-cancers (HGSOC). Because scant information is currently available in the literature on the potential negative effect of PIK3CA mutations on the activity of afatinib, in this study we evaluate for the first time the role of oncogenic PIK3CA mutations as a potential mechanism of resistance to afatinib in HGSOC and USC overexpressing HER2/neu.MethodsWe used six whole-exome-sequenced primary HGSOC/USC cell-lines and three xenografts overexpressing HER2/neu and harboring mutated or wild-type PIK3CA/PIK3R1 genes to evaluate the role of PI3K-mutations as potential mechanism of resistance to afatinib, an FDA-approved pan-c-erb-inhibitor in clinical trials in USC. Primary-USC harboring wild-type-PIK3CA gene was transfected with plasmids encoding oncogenic PIK3CA-mutations (H1047R/E545K). The effect of afatinib on HER2/PI3K/AKT/mTOR pathway was evaluated by immunoblotting.ResultsWe found PI3K wild-type cell-lines to be significantly more sensitive (lower IC50) than PI3K-mutated cell-lines p = 0.004). In vivo, xenografts of primary cell-line USC-ARK2, transfected with the PIK3CA-H1047R or E545K hotspot-mutations, exhibited significantly more rapid tumor growth when treated with afatinib, compared to mice harboring ARK2-tumors transfected with wild-type-PIK3CA (p = 0.041 and 0.001, respectively). By western-blot, afatinib effectively reduced total and phospho-HER2 proteins in all cell-lines. However, H1047R/E545K-PIK3CA-transfected-ARK2-cells demonstrated a greater compensatory increase in phosphorylated-AKT proteins after afatinib exposure when compared to controls ARK2.ConclusionsOncogenic PI3K mutations may represent a major mechanism of resistance to afatinib. Combinations of c-erb with PIK3CA, AKT or mTOR inhibitors may be necessary to more efficiently block the PIK3CA/AKT/mTOR pathway.

Dataset Information

Oncogenic PI3K mutations lead to NF-?B-dependent cytokine expression following growth factor deprivation.

Publications

Oncogenic PI3K mutations lead to NF-κB-dependent cytokine expression following growth factor deprivation.

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