An Essential Role for the Tumor-Suppressor Merlin in Regulating Fatty Acid Synthesis.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas, and meningiomas. Mutational inactivation of the NF2 gene encoding the protein Merlin is found in most sporadic and inherited schwannomas, but the molecular mechanisms underlying neoplastic changes in schwannoma cells remain unclear. We report here that Nf2-deficient cells display elevated expression levels of key enzymes involved in lipogenesis and that this upregulation is caused by increased activity of Torc1. Inhibition or knockdown of fatty acid synthase (FASN), the enzyme that catalyzes the formation of palmitic acid from malonyl-CoA, drove NF2-deficient cells into apoptosis. Treatment of NF2-mutant cells with agents that inhibit the production of malonyl-CoA reduced their sensitivity to FASN inhibitors. Collectively, these results suggest that the altered lipid metabolism found in NF2-mutant cells renders them sensitive to elevated levels of malonyl-CoA, as occurs following blockade of FASN, suggesting new targeted strategies in the treatment of NF2-deficient tumors. Cancer Res; 77(18); 5026-38. ©2017 AACR.

Medium throughput biochemical compound screening identifies novel agents for pharmacotherapy of neurofibromatosis type 1.

The variable manifestation of phenotypes that occur in patients with neurofibromatosis type 1 (NF1) includes benign and malignant neurocutaneous tumors for which no adequate treatment exists. Cell-based screening of known bioactive compounds library identified the protein phosphatase 2A (PP2A) inhibitor Cantharidin and the L-type calcium channel blocker Nifedipine as potential candidates for NF1 pharmacotherapy. Validation of screening results using human NF1-associated malignant peripheral nerve sheath tumor (MPNST) cells showed that Cantharidin effectively impeded MPNST cell growth, while Nifedipine treatment significantly decreased local tumor growth in an MPNST xenograft animal model. These data suggest that inhibitors of PP2A, as well as calcium channel blockers, might be used in broader MPNST preclinical studies as single agents or in combinatorial therapeutic strategies.

p21-Activated kinase 1 is required for efficient tumor formation and progression in a Ras-mediated skin cancer model.

The RAS genes are the most commonly mutated oncogenes in human cancer and present a particular therapeutic dilemma, as direct targeting of Ras proteins by small molecules has proved difficult. Signaling pathways downstream of Ras, in particular Raf/Mek/Erk and PI3K/Akt/mTOR, are dominated by lipid and protein kinases that provide attractive alternate targets in Ras-driven tumors. As p21-activated kinase 1 (Pak1) has been shown to regulate both these signaling pathways and is itself upregulated in many human cancers, we assessed the role of Pak1 in Ras-driven skin cancer. In human squamous cell carcinoma (SCC), we found a strong positive correlation between advanced stage and grade and PAK1 expression. Using a mouse model of Kras-driven SCC, we showed that deletion of the mouse Pak1 gene led to markedly decreased tumorigenesis and progression, accompanied by near total loss of Erk and Akt activity. Treatment of Kras(G12D) mice with either of two distinct small molecule Pak inhibitors (PF3758309 and FRAX597) caused tumor regression and loss of Erk and Akt activity. Tumor regression was also seen in mice treated with a specific Mek inhibitor, but not with an Akt inhibitor. These findings establish Pak1 as a new target in KRAS-driven tumors and suggest a mechanism of action through the Erk, but not the Akt, signaling pathway.

p21-Activated kinases are required for transformation in a cell-based model of neurofibromatosis type 2.

BACKGROUND: NF2 is an autosomal dominant disease characterized by development of bilateral vestibular schwannomas and other benign tumors in central nervous system. Loss of the NF2 gene product, Merlin, leads to aberrant Schwann cell proliferation, motility, and survival, but the mechanisms by which this tumor suppressor functions remain unclear. One well-defined target of Merlin is the group I family of p21-activated kinases, which are allosterically inhibited by Merlin and which, when activated, stimulate cell cycle progression, motility, and increased survival. Here, we examine the effect of Pak inhibition on cells with diminished Merlin function. METHODOLOGY/PRINCIPAL FINDINGS: Using a specific peptide inhibitor of group I Paks, we show that loss of Pak activity restores normal cell movement in cells lacking Merlin function. In addition, xenografts of such cells form fewer and smaller tumors than do cells without Pak inhibition. However, in tumors, loss of Pak activity does not reduce Erk or Akt activity, two signaling proteins that are thought to mediate Pak function in growth factor pathways. CONCLUSIONS/SIGNIFICANCE: These results suggest that Pak functions in novel signaling pathways in NF2, and may serve as a useful therapeutic target in this disease.