KLF4K409Q–mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment

Abstract

Meningioma represents the most common primary brain tumor in adults. Recently several non-NF2 mutations in meningioma have been identified and correlated with certain pathological subtypes, locations and clinical observations. Alterations of cellular pathways due to these mutations, however, have largely remained elusive. Here we report that the Krueppel like factor 4 (KLF4)-K409Q mutation in skull base meningiomas triggers a distinct tumor phenotype. Transcriptomic analysis of 17 meningioma samples revealed that KLF4 K409Q mutated tumors harbor an upregulation of hypoxia dependent pathways. Detailed in vitro investigation further showed that the KLF4 K409Q mutation induces HIF-1α through the reduction of prolyl hydroxylase activity and causes an upregulation of downstream HIF-1α targets. Finally, we demonstrate that KLF4 K409Q mutated tumors are susceptible to mTOR inhibition by Temsirolimus. Taken together, our data link the KLF4 K409Q mediated upregulation of HIF pathways to the clinical and biological characteristics of these skull base meningiomas possibly opening new therapeutic avenues for this distinct meningioma subtype.

Advances in meningioma genomics, proteomics, and epigenetics: insights into biomarker identification and targeted therapies

“…TRAF7 mutations are present in approximately 25% of sporadic meningiomas, and studies have revealed they are mutually exclusive from NF2 mutant tumors, yet larger studies are need to confirm exclusivity of TRAF7 mutant tumors. TRAF7 mutations also present with mutations in AKT1 or KLF4, especially those KLF4 mutations as a result of the recurrent K409Q mutation [33]. Tumors with mutations in both TRAF7 and KLF4 are most often found in secretory meningiomas with TRAF7 mutant tumors having a predilection for the anterior skull base [24].…”

Molecular profiling of pediatric meningiomas shows tumor characteristics distinct from adult meningiomas

“…DNA extracted from FFPE tissue was processed using standard procedures as previously described [ 42 ]. We analyzed all meningiomas for known hotspot mutations in the genes SMO (L412F and W535L) [ 4 ], AKT1 (E17K) [ 42 ], and KLF4 (K409Q) [ 41 ].…”

AKT1E17K‐mutated meningioma cell lines respond to treatment with the AKT inhibitor AZD5363

“…HEK293T cells (DSMZ, Braunschweig) were transfected using FuGene® HD transfection reagent (Promega, Mannheim, Germany) with pLV[Exp]‐Bsd‐EF1A > hAKT1[NM_005163.2] and pLV[Exp]‐Bsd‐EF1A > [hAKT1[NM_005163.2]*(E17K) (VectorBuilder) in combination with lentiviral packaging plasmid mix pC‐Pack 2 (Cellecta) as reported 30 . Both plasmids contain the same lentiviral vector backbone.…”

“…The head skin was cut longitudinally. A single hole was drilled 1.5 mm anterior of the bregma and 2 mm on the right side from the sagittal suture and 0.5 × 10 5 transfected IOMM‐Lee cells ( AKT1 wt or AKT1 E17K ) in 0.5‐μl PBS were deposited above the skull base bone (about 7.5 mm in depth) 30 …”