Frequent AKT1E17K mutations in skull base meningiomas are associated with mTOR and ERK1/2 activation and reduced time to tumor recurrence

Abstract

Background: Skull base meningiomas are considered to be difficult for surgical treatment. We wondered whether genetic alterations recently identified in benign non-NF2-mutated World Health Organization (WHO) grade I meningiomas are related to clinical features of skull base meningiomas and whether druggable signaling pathways are activated.

Methods: We analyzed 93 skull base meningiomas (82 WHO grade I, 11 WHO grade II) for mutations of hot spots or the most relevant exons of AKT1, KLF4/TRAF7, SMO, PI3K, and the TERT promoter.

Results: The AKT1E17K mutation was present in 31% of patients and was related to meningothelial histology. AKT1E17K had a negative effect on the time to tumor recurrence. Analyses of activated signaling proteins revealed among AKT1E17K tumors a significantly higher rate of phospho-mammalian target of rapamycin (mTOR) and phospho-p70S6K+ tumors. AKT1E17K tumors with immunoexpression of phospho-extracellular signal-regulated kinase 1 or 2 (ERK1/2) were characterized by significantly shorter time to tumor recurrence compared with AKT1wt tumors expressing phospho-ERK1/2 (P = .046). KLF4 mutations (K409Q) were present in 11.8% of cases, with significant association to the secretory/transitional subtype (P < .001). The presence of the KLF4 K409Q mutation was associated with favorable outcome. One phosphatidylinositol-3 kinase (PI3K) mutation but no SMO or TERT promoter mutation was found.

Conclusions: AKT1E17K mutation is frequent in skull base meningiomas, results in activation of the mTOR and ERK1/2 signaling pathways, and has negative impact on tumor recurrence. Patients with skull base meningiomas with AKT1E17K mutation might benefit from additional treatment targeting the mTOR pathway. Generally, the PI3K-Akt-mTOR axis might be a potential target for kinase inhibitors in these tumors.

Keywords: AKT1; KLF4; meningioma; skull base.

Fig. 1

AKT1 ^E17K mutation and mTOR signaling in skull base meningiomas. (A) Example for the detection of the AKT1^E17K mutation by Sanger sequencing. (B) Kaplan–Meier plot of recurrence-free survival for patients with skull base meningiomas harboring AKT1^E17K (N = 29, 6 events) or AKT1^wt (N = 64, 6 events; P = .094 [log rank test]) (see also results of Cox regression analysis in text). (C) Examples for immunoexpression of phospho-mTOR, phospho-p70S6K, and phospho-4EBP1 in relation to the AKT1 mutation status (AKT1^wt [left panel] or AKT1^E17K [right panel]). Scoring of immunostaining is given below [each scale bar = 100 µm]. (D) Kaplan–Meier plots with separation for immunoexpression of phospho-mTOR (upper figure) or phospho-4EBP1 (lower figure). Case numbers and events are given in Supplementary Table S2.

Fig. 2

AKT1 ^E17K mutation and ERK1/2 signaling in skull base meningiomas. (A) Examples for immunoexpression of phospho-ERK1/2 in relation to the AKT1 mutation status (AKT1^wt [left panel, scale bar = 100 µm] or AKT1^E17K [right panel, scale bar = 50 µm]). Scoring of immunostaining is given below. (B) Kaplan–Meier plots showing differences between phospho-ERK1/2 positive versus negative tumors in relation to the AKT1 mutation status (AKT1^wt or AKT1^E17K). Case numbers and events are given in Supplementary Table S1.

Fig. 3

KLF4 mutation in skull base meningioma. (A) Example for detection of the KLF4 mutation. (B) Kaplan–Meier plots showing differences in terms of tumor recurrence depending on the KLF4 mutation (KLF4^wt: N = 82, 12 events; KLF4^K409Q: N = 11, 0 events [log-rank test]).

Fig. 4

Distribution of AKT1^E17K (red dots), KLF4 (blue dots), and combined KLF4/TRAF7 mutations (green dots) at the skull base.

Fig. 5

The network of kinase reactions (phosphorylations), which transmit pro-proliferative signals from receptor tyrosine kinases (RTKs) along the PI3K-Akt-mTOR or ERK1/2 pathways is drafted in this scheme. A very important RTK in meningiomas is platelet-derived growth factor receptor (PDGFR), especially the predominant form, PDGFR-ß. Proliferation of meningioma cells is stimulated by PDGF-mediated activation of the receptor and subsequent kinase reactions of PI3K and AKT1. The latter partially exerts its effects via a downstream pathway involving mTOR complex 1 (mTORC1) and its direct targets p70S6K and 4EBP1. Activation of AKT1, which may occur either by upstream kinases or eventually by the mutation E17K, leads to an activation of the downstream mTOR pathway, detectable as an enhanced expression of the phosphorylated forms of mTOR and p70S6K, while the activation is reflected in a lower phosphorylation of 4EBP1. An alternative route of mitogenic signal transduction via ERK1/2 is possible and is reflected by a higher abundance of phosphorylated ERK1/2. This pathway can potentially be crosslinked with the first one (activation of mTORC1 by ERK1/2).