A high-throughput kinome screen reveals serum/glucocorticoid-regulated kinase 1 as a therapeutic target for NF2-deficient meningiomas

Abstract

Meningiomas are the most common primary intracranial adult tumor. All Neurofibromatosis 2 (NF2)-associated meningiomas and ~60% of sporadic meningiomas show loss of NF2 tumor suppressor protein. There are no effective medical therapies for progressive and recurrent meningiomas. Our previous work demonstrated aberrant activation of mTORC1 signaling that led to ongoing clinical trials with rapamycin analogs for NF2 and sporadic meningioma patients. Here we performed a high-throughput kinome screen to identify kinases responsible for mTORC1 pathway activation in NF2-deficient meningioma cells. Among the emerging top candidates were the mTORC2-specific target serum/glucocorticoid-regulated kinase 1 (SGK1) and p21-activated kinase 1 (PAK1). In NF2-deficient meningioma cells, inhibition of SGK1 rescues mTORC1 activation, and SGK1 activation is sensitive to dual mTORC1/2 inhibitor AZD2014, but not to rapamycin. PAK1 inhibition also leads to attenuated mTORC1 but not mTORC2 signaling, suggesting that mTORC2/SGK1 and Rac1/PAK1 pathways are independently responsible for mTORC1 activation in NF2-deficient meningiomas. Using CRISPR-Cas9 genome editing, we generated isogenic human arachnoidal cell lines (ACs), the origin cell type for meningiomas, expressing or lacking NF2. NF2-null CRISPR ACs recapitulate the signaling of NF2-deficient meningioma cells. Interestingly, we observe increased SGK1 transcription and protein expression in NF2-CRISPR ACs and in primary NF2-negative meningioma lines. Moreover, we demonstrate that the dual mTORC1/mTORC2 inhibitor, AZD2014 is superior to rapamycin and PAK inhibitor FRAX597 in blocking proliferation of meningioma cells. Importantly, AZD2014 is currently in use in several clinical trials of cancer. Therefore, we believe that AZD2014 may provide therapeutic advantage over rapalogs for recurrent and progressive meningiomas.

Serum and Glucocorticoid Inducible Kinase 1-Sensitive Survival, Proliferation and Migration of Rhabdomyosarcoma Cells

“…Moreover, the sensitivity of RMS cell lines to the cytotoxic drug doxorubicin was enhanced, which is in complete accordance with reports that show SGK1 supporting cell proliferation, stimulating their migration and counteracting apoptosis in diverse tumor cell types [16, 29], including colorectal carcinoma [11-13, 16, 45], hepatocellular carcinoma [17, 18], breast cancer [18-20], prostate cancer [21, 22], glioblastoma [23-25], non-small cell lung cancer [26], meningiomas [27] and medulloblastoma [28]. …”

“…Mechanisms conferring tumor cell survival and therapy resistance include the serum & glucocorticoid inducible kinase SGK1, initially identified in mammary tumor cells [8-14], yet then found as being ubiquitously expressed with strong emphasis in skeletal muscle [15] and highly upregulated in different tumors such as colonic cancer [16], hepatocellular carcinoma [17, 18], breast cancer [18-20], prostate cancer [21, 22], glioblastoma [23-25], non-small cell lung cancer [26], meningiomas [27], and medulloblastoma [28]. Several studies demonstrate a pivotal role for SGK1 in cell survival, cell proliferation and migration of tumor cells [16, 29].…”

High p‐mTOR expression is associated with recurrence and shorter disease‐free survival in atypical meningiomas

“…Whether mTOR Ser 2481 is expressed in atypical meningiomas still remains to be verified. However, the higher efficacy of the dual mTORC1/mTORC2 inhibitors compared to rapamycin in blocking the proliferation of meningioma cells is strongly in favor of this hypothesis. Finally, this study still leaves unsolved whether p‐mTOR expression is maintained in recurrent meningiomas, and whether it could represent a therapeutic target also in this setting.…”

Clinicopathological signature of p21-activated kinase 1 in prostate cancer and its regulation of proliferation and autophagy via the mTOR signaling pathway

“…Roberta L. Beauchamp et al [41] reported that independent activation of SGK1 and PAK1 may be partly responsible for the mTORC1 activation in NF2-deficient meningioma cells, and the group I PAK inhibitor FRAX597 may be improper for treatment for higher concentrations needed. Treatment with specific inhibitors of growth signaling pathways (MEK/PI3K/mTOR) demonstrated that in normal diploid colon epithelial cells (HCEC-1CT), PAK1 expression is regulated by MEK, PI3K, and mTOR [42].…”