ALBERT

Description: Mechanistic target of rapamycin complex 1 (mTORC1) is a central integrator of nutrient and growth factor inputs that controls cell growth in all eukaryotes. Rapamycin and its analogs (rapalogs) have been approved for the treatment of relapsed mantle cell lymphoma. A large proportion of aggressive B-cell lymphoma patients, however, respond poorly to rapalogs. The second generation of mTOR inhibitors function as ATP-competitive inhibitors (TORi), directly targeting the mTOR catalytic site. TORis have been proven to be more effective than rapalogs in cancer treatment. However, the mechanism underlying the cytotoxic effect of TORis in aggressive B-cell lymphomas remains unclear. In this study, we demonstrated that TORi-induced apoptosis is predominantly dependent on loss of mTORC1-mediated 4EBP phosphorylation. Knocking out Rictor, a key component of mTORC2, or inhibiting p70S6K has little effect on TORi-induced apoptosis. In contrast, increasing the EIF4E:4EBP ratio by either overexpressing EIF4E or knocking out 4EBP1/2 protected lymphoma cells from TORi-induced cytotoxicity. Furthermore, down-regulation of MCL1 and BCL-XL expression plays an important role in TORi-induced apoptosis whereas BCL-2, in cells with high expression, confers resistance to TORi treatment. Based on the mechanism study, we demonstrated that BH3 profiling, primarily NOXA and HRK stimulation, can effectively predict the cytotoxicity of the TORi in lymphoma cells. Also, in combination with pro-apoptotic drugs, especially BCL-2 inhibitors, the TORi exerted powerful anti-tumor effects both in vitro and in vivo. Taken together, this study provides mechanistic insight in TORi treatment in aggressive B-cell lymphoma and identified a mean to predict and improve its effectiveness clinically. Disclosures No relevant conflicts of interest to declare.

Description: mTORC1 (mammalian target of rapamycin complex 1) plays a central role in integrating nutrient and growth factor inputs to control cell growth in all eukaryotes and is commonly deregulated in human cancers. Inhibition of mTORC1 is a promising strategy in lymphoma therapy. However, only a few drugs, such as rapamycin and its analogs (rapalogs), have been approved for treatment in a limited number of cancer types, due to their incomplete and nonspecific inhibition of mTORC1 as well as their limited effects toward the 4EBP1 pathway. 4EBP1 pathway regulates protein translation which is considered to be crucial in cancer cell survival and proliferation. In this study, we used the glycolysis inhibitor 2-deoxyglucose (2-DG) together with the mitochondrial respiratory inhibitor metformin to treat aggressive B cell lymphoma cells in vitro and in vivo. We found that the combined treatment inhibited mTORC1 and its major downstream targets, including 4EBP1. As a result, combined treatment significantly inhibited tumor cell growth and survival by the inhibition of 5’ cap-dependent translation involving lymphoma associated oncogenes such as MCL-1, BCL-XL and Cyclin D1. Moreover, the combination of 2-DG and metformin suppressed tumor growth in B cell lymphoma xenograft mouse models. Although the combined treatment dramatically decreased cellular ATP levels, mTORC1 inhibition was independent of AMPK activity but instead resulted from inhibitory effects on Rag-GTPases, which are upstream activators of mTORC1. Given that both 2-DG and metformin have been used in clinical diagnosis or treatment for decades, the combination of the two drugs hold promise as a new strategy to treat aggressive B cell lymphoma. Disclosures: No relevant conflicts of interest to declare.

Description: Burkitt lymphoma (BL) is the most common non-Hodgkin lymphoma (NHL) in children. Although it accounts for only 1-5% of NHL in adults, approximately 60% of the BL cases diagnosed each year in western countries occur in patients 〉40 years of age. Although adult and pediatric BL cases are indistinguishable by molecular classification, pediatric patients have a significantly better outcome than adults. While translocation of MYC to the immunoglobulin heavy or light chain genes is characteristic of pediatric and adult BL, genetic differences may contribute to the superior clinical outcome of childhood cases. Therefore, we aimed to identify the spectrum of additional genetic abnormalities that occur in adult and pediatric BL. Copy number analysis, gene expression profiling (GEP), and targeted sequencing of ~400 genes known to be mutated in NHLs were performed on a cohort of molecularly defined BL samples. Copy number abnormalities (CNAs) were identified by the Affymetrix 250k NspI SNP array in 73 BL tumors (28 adult, 45 pediatric), and sequencing was performed on 52 BLs (21 adult, 31 pediatric). Pediatric cases had fewer CNAs than adults. The most common focal abnormality identified was a gain on 13q31.3 encompassing MIR17HG. It was more frequent in adult compared to pediatric cases (35% vs 16%, p=0.085) and was associated with increased expression of miR-17~92 cluster members; and among adults, patients with this gain trended towards worse overall survival, though the number of cases with available information was small. Gain of 8q was found in ~20% of adult cases, but in no pediatric cases. Surprisingly, cases with 8q gain had significantly lower MYC mRNA expression (p〈 0.001) and lower protein expression. In cases with MYC gain 0/4 cases were positive for MYC protein expression by immunohistochemistry; in contrast,6/10 cases with no MYC gain were positive for MYC expression. This suggests that gain of 8q is driven by another gene in the region. Additional genetic alterations included gains of genomic loci encompassing MCL1 and MDM4 (1q21-24) and losses encompassing RB1, p53 and CDKN2A/CDKN2B. Pathway analysis of genes differentially expressed by CN status showed an enrichment of genes involved in cell cycle regulation, the p53 signaling pathway, and the ubiquitin proteasome pathway. The frequencies of mutations in commonly mutated genes including MYC, ID3, TP53, CCND3, DDX3X, ARID1A, and TCF3 were not significantly different in adult and pediatric BL. However, BCL2, (43%, p

Description: Diffuse large B-cell lymphoma (DLBCL) displays significant heterogeneity with regard to clinical, pathological, and genetic features. Using gene expression profiling, we have delineated 3 molecular subgroups within DLBCL: germinal center B cells (GCB-DLBCL), activated B cells (ABC-DLBCL), and primary mediastinal B-cell lymphoma (PMBL),while these defined subgroups show characteristic mutation profiles and oncogenic pathways, a small set of cases of DLBCL still remain "unclassifiable" (UC). Burkitt lymphoma (BL) is characterized by the t(8;14)(q24;q32) with distinct morphological and immunophenotypic features. The diagnostic distinction between BL and DLBCL is challenging in a subset of cases that have overlapping morphological, immunohistochemical, and even molecular features, but is crucial for effective therapy. The identification of long non-coding RNA (lncRNA) has added another critical component to cancer biology. LncRNAs are defined as a distinct set of non-protein coding transcripts longer than 200 nucleotides. The functions of a few lncRNAs have been recently elucidated of which some are thought to regulate gene-specific transcription. The goal of the current study was to identify reliable lncRNA signatures for the BL and DLBCL subgroups and evaluate their usefulness as prognostic biomarkers. We examined the expression of lncRNAs from our earlier studies using Affymetrix-HG-U133 plus 2 arrays to distinguish unique gene expression profiles between BL and DLBCL (PMID: 27292966). In the initial analysis, we compared BL (n=77) with DLBCL (n=474) and identified 275 differentially expressed lncRNAs (p=0.005, fold change〉1.5). There was high expression of TCL6 and DDX-AS11 in BL. We confirmed the microarray results for TCL6 and DDX-AS11 by qRT-PCR in a subset of cases. We further tested whether expression of TCL6 and DDX-AS11 was regulated by the MYC oncogene and observed significant downregulation of these transcripts upon CRISPR/cas9 mediated deletion of the MYC promoter in the Raji cell line. We also sought to identify GCB-DLBCL and ABC-DLBCL associated lncRNAs. We observed 36 lncRNAs highly expressed in ABC-DLBCL and 40 lncRNAs highly expressed in GCB-DLBCL (P=0.005, fold change〉1.5). Of the differentially expressed lncRNAs, lnc00487 and DUBR were upregulated in GCB-DLBCL, whereas lnc00944 and FUT8 were upregulated ABC-DLBCL. The observed expression differences were validated in ABC-DLBCL and GCB-DLBCL cell lines. The differentially expressed LncRNAs were also validated in other DLBCL cohorts. LncRNA00487 expression was associated with superior clinical outcome in DLBCL series treated with Rituximab (R)-CHOP (p=0.01), and gene expression and overall survival (OS) were validated in another DLBCL series treated with R-CHOP (PMID:22437443). In the present study, we found that lncRNAs are differentially expressed in aggressive B cell lymphoma and could be useful as diagnostic or prognostic markers. They may play an important role in lymphoma biology and further studies of their functions are warranted. Disclosures No relevant conflicts of interest to declare.

Description: Background: c-MYC (MYC) is commonly dysregulated in aggressive B cell lymphomas. MYC associated lymphoma, especially Double Hit lymphoma (DHL) and Double-Expression Lymphoma (DEL) which are characterized by MYC and BCL2 dual overexpression usually present with the inferior outcome as rapid disease progression and poor response to standard chemotherapy regimen. Nevertheless, MYC is considered as an "undruggable" target and targeting strategies such as suppressing MYC transcription by bromodomain (BRD)-4 inhibitors have been widely investigated in both preclinical models and clinical trials. However, increasing evidence has shown that lymphoma cells displayed a wide range of resistance to BRD-4 inhibition, due to transcription adaptation or kinome reprogramming. Hence, alternative approaches for suppressing MYC or its function are urgently needed. Strategies directed against oncoprotein translation may efficiently repress key oncoproteins regardless of the abundant MYC mRNA due to genetic aberrations and secondary transcription up-regulated by MYC. Rocaglate is a class of natural products derived from plants of the Aglaia genus that have been demonstrated to potently inhibit protein translation initiation via eIF4A. The use of rocaglates for anti-cancer treatment was limited due to the scarcity and instability of these natural products e.g. Silvestrol. Recent chemical modification and screening studies have unveiled a few synthetic rocaglates that are more potent than Silvestrol such as SDS-1-021-(−), which unlocked the potential use of rocaglates for clinical applications. Methods and Results: To probe effective reagents for MYC-driven lymphoma, a screening of 50 drugs targeting common oncogenic pathways and tumorigenic machinery was performed in two isogenic B-lymphoma lines. Several protein translation inhibitors, such as mTOR kinase inhibitors (TORKi), and eIF4A inhibitor Silvestrol were identified as the most potent drugs in all of the tested cells. Further, we found that Silvestrol but not TORKi efficiently repressed MYC protein translation in MYC-driven B lymphoma cells, whereas neither of them inhibited BCL2 expression. Moreover, we demonstrated that eIF4E knockdown or eIF4E/eIF4G disruptor Briciclib did not significantly affect MYC expression, whereas eIF4A inhibitor hippuristanol and rocaglates derivate SDS-1-021-(−) diminished MYC expression similar to that observed in Silvestrol treated cells. By using dual luciferase assay, we demonstrated that rocaglates had stronger cap-dependent and IRES translation inhibition than TORKi in lymphoma cells. Next, by native RNA immunoprecipitation and siRNA knocking down, we found that rocaglates repressed MYC translation not only via eIF4A1 but also via eIF4A2, however, with different underlying mechanisms. Furthermore, to explore the molecular targets of rocaglates treatment in B cell lymphoma, we performed TMT-Mass Spectrometry which identified multiple oncoproteins including NEK2, MYC, MCL1, TCF3, BCL6, PLK1, AURKA, and WEE1 were significantly down-regulated by SDS-1-021-(−) treatment. Finally, we demonstrated that SDS-1-021-(−) is highly potent as a single agent and synergized with ABT199 at a low dose (0.2mg/kg) in PDX models with DHL/DEL. Brief summary : Our pre-clinical study provided strong evidence that rocaglates but not TORKi efficiently suppress MYC protein translation because 1). Rocaglates exhibit strong inhibition on both Cap- and IRES-dependent translation, 2). Rocaglates decrease PLK1 and AURKA/B thus destabilizing MYC protein. The synthetic rocaglate SDS-1-021-(−) is a potent agent that exhibits significant synergistic killing effect with ABT199 on DHL/DEL cells in the pre-clinical animal study. Figure Figure. Disclosures Lunning: TG Therapeutics: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Astra-Zeneca: Consultancy; Genzyme: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Spectrum: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; Portola: Consultancy; Kite: Consultancy; Juno: Consultancy; Janssen: Consultancy; Verastem: Consultancy. Vose:Novartis: Honoraria, Research Funding; Epizyme: Honoraria; Incyte Corp.: Research Funding; Bristol Myers Squibb: Research Funding; Kite Pharma: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Abbvie: Honoraria; Legend Pharmaceuticals: Honoraria; Seattle Genetics, Inc.: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding; Roche: Honoraria.

Description: Key Points Adult-mBLs have distinct and more frequent DNA copy number abnormalities compared with pediatric-mBL. Comprehensive genomic analysis revealed that the BCR signaling pathway is a potential therapeutic target in adult-mBL.

Description: Background: c-MYC is a transcription factor that promotes oncogenesis by activating and repressing its target genes that control cell growth, metabolism, and proliferation. MYC is deregulated in a large proportion of aggressive B-cell lymphomas. A typical example is the Double-Hit Lymphoma (DHL) and Double-Expression Lymphoma (DEL) which present with a rapidly progressing clinical course, refractory to treatment, poor clinical outcome, and currently considered incurable. Nevertheless, MYC is considered as an "undruggable" target since it has no "active site" amenable to binding by conventional small molecule inhibitors. Moreover, MYC has a broad spectrum of functions in cell proliferation, survival, metabolism, and others, so direct inhibition would likely cause severe side effects. Besides direct inhibition, another practical strategy is to target druggable proteins that are essential for the viability of MYC-driven tumors, inducing MYC-dependent "synthetic lethality". The advantage of such approach is a capability of killing tumor cells discriminately, while leaving non-tumor cells intact or less influenced. This study is designed to identify such targets and explore practical novel strategies to treat MYC-driven lymphomas, especially DHL/DEL. Methods and Results: By integrating activity-based proteomic profiling and drug screens in isogenic MYC on/off lymphoma cells, we identified polo-like kinase-1 (PLK1) as an essential regulator of the MYC-dependent kinome in DHL/DEL. Notably, PLK1 was expressed at high levels in DHL, correlated with MYC expression and connoted poor outcome. Further, PLK1 is directly activated by MYC on transcriptional level and in turn, PLK1 signaling augmented MYC protein stability by promoting its phosphorylation and suppressing its degradation. Thus, MYC and PLK1 form a feed-forward circuit in lymphoma cells. Finally, both in vitro and in vivo studies demonstrated that inhibition of PLK1 triggered degradation of MYC and of the anti-apoptotic protein MCL1, and PLK1 inhibitors showed synergy with BCL-2 antagonists in blocking DHL/DEL cell growth, survival, and tumorigenicity. These data support that PLK1 is a promising therapeutic target in MYC-driven lymphomas. Brief summary: Functional pharmacoproteomics identified PLK1 as a therapeutic vulnerability for MYC-driven lymphoma, which was a synthetic lethal for DHL/DEL when targeted with BCL-2 inhibitors. Disclosures Vose: Roche: Honoraria; Merck Sharp & Dohme Corp.: Research Funding; Acerta Pharma: Research Funding; Seattle Genetics, Inc.: Research Funding; Novartis: Honoraria, Research Funding; Kite Pharma: Research Funding; Bristol Myers Squibb: Research Funding; Epizyme: Honoraria; Legend Pharmaceuticals: Honoraria; Abbvie: Honoraria; Celgene: Research Funding; Incyte Corp.: Research Funding.

Description: BACKGROUND: Interleukin-22 (IL-22) was recently discovered as a T-cell derived cytokine that belongs to the IL-10 gene family. It has been shown that IL-22 can promote cell proliferation and activate several oncogenic pathways including STAT3, MAPK and AKT signaling. IL-22 exerts its function by binding to its heterodimeric receptor complex which is composed of IL-22 receptor (R) 1 and IL-10R2. IL-22R1 is restricted and barely detected in normal immune cells including B and T cells. In the current study, we sought to determine whether IL-22 plays a part in the development of diffuse large B-cell lymphoma (DLBCL). METHODS: Plasma IL-22 level was measured in newly diagnosed patients with DLBCL and normal individuals by ELISA assay. We also assessed the expression of IL-22R1 in FFPE sample and DLBCL cell lines (TMD8, OCI-LY3, SUDHL16, OCI-LY1) by immunohistochemistry and immunofluorescence staining respectively. Immunoblotting was performed to determine changes of signaling pathways in cell lines upon the treatment with IL-22 recombinant protein. RESULTS: The plasma IL-22 concentration was significantly increased in newly diagnosed DLBCL patients (n=12) compared with normal individuals (n=26, P= 0.0177). IL-22R1 protein was expressed in all of the four DLBCL cell lines, while not all but some of the primary tumor samples expressed it on membranes of tumor cells. Using immunoblotting, we demonstrated a substantial increase of pSTAT3 level with the treatment of IL-22 in ABC-DLBCL cell lines TMD8 and OCI-LY3, while no pSTAT3 was detectable in GCB-DLBCL cell lines SUDHL16 and OCI-LY1. Interestingly, upon IL-22 stimulation, the p-ERK1/2 level was increased shortly and quickly returned to the normal level in TMD8 cells, and steadily increased in LY3 cells during 30 min of treatment. However, there was no change about p-ERK1/2 in SUDHL16 and OCI-LY1 cells after IL-22 treatment. CONCLUSIONS: Our current study has shown the aberrant expression of IL-22R1 in DLBCL. And recombinant IL-22 protein increased the activation of STAT3 and ERK1/2 in ABC rather than GCB-DLBCL cell lines. For the first time, we suggested the importance of IL-22 and its receptor IL-22R1 pathway in ABC-DLBCL, which warrants further studies. Figure 1. The expression of IL-22R1 in DLBCL cell lines was detected by using immunofluorescence staining. Disclosures No relevant conflicts of interest to declare.

Description: The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) is a very aggressive lymphoma characterized by constitutive NF-kB activation, but whether miRNAs dysfunction contributes to this event, and their exact function and mechanism remain unclear. Starting from an integrative screening strategy, we revealed that there were some interactions between the NF-kB signaling and miR-17~92 cluster, which was essential for B-cell development and commonly gained and/or overexpressed in ABC-DLBCL. Several important NF-kB negative regulators including TNFAIP3 (A20), CYLD and Rnf11 were predicted and validated to be the direct targets of miR-17~92. Conditional knock-down of miR-17~92 using sponge could suppress NF-kB activity and elevate the A20, CYLD and Rnf11 expression in 293T cells. Furthermore, we demonstrated that enforced overexpression of miR-17~92 could also decrease the A20, CYLD and Rnf11 expression in ABC-DLBCL cells. Conditional overexpression of miR-17~92 could promote ABC-DLBCL cells growth, accelerate the cells G1/G0 phase to S phase transition, and suppress NF-kB inhibitor-induced apoptosis. Conversely, conditional knock-down of miR-17~92 could inhibit ABC-DLBCL cells growth and sensitize the cells to NF-kB inhibitor-induced apoptosis. The miR-17~92 could induce the IkB-a and NF-kB p65 phosphorylation, leading to the NF-kB activation and aberrant expression of NF-kB transcriptional target genes. However, miR-17~92 did not regulate the NF-kB p52/p100 phosphorylation. Overexpression of miR-17~92 enhanced K63-linked ubiquitination and reduced K48-linked ubiquitination of the TNFa receptor 1 complex including RIP1. Importantly, we found that high expression level of miR-17~92 was associated with poorer survival in ABC-DLBCL patients. Our results uncovered a novel mechanism for the canonical but not the non-canonical transcription factor NF-kB pathway by modulation of miR-17~92 in ABC-DLBCL, and suggested that targeting the miR-17~92 might be novel bio-therapeutic strategies, which could be single-agent or combined with NF-kB inhibitor treatment, for ABC-DLBCL patients. Figure 1. Inhibition of miR-17~92 blocks the activity of NF-kB in HER293T cells: (A) The schematic representation of reporter constructs involved in assay. (B) HEK293T cells were co-transfected with Dul-Luciferase reporter constructs and the miR-17~92 sponge plasmid. TNF-a stimulation or without stimulation for 18 h. Figure 1. Inhibition of miR-17~92 blocks the activity of NF-kB in HER293T cells: (A) The schematic representation of reporter constructs involved in assay. (B) HEK293T cells were co-transfected with Dul-Luciferase reporter constructs and the miR-17~92 sponge plasmid. TNF-a stimulation or without stimulation for 18 h. Figure 2. miR-17~92 directly regulates A20, CYLD and Rnf11 in ABC-DLBCL cells. (A) Fluorescence images of tranduced ABC-DLBCL cells. (B) Expression of sponge or miR-17~92 in tranduced ABC-DLBCL cells. (C) Inhibition of miR-17~92 increase the expression of A20, CYLD and Rnf11. Overexpression of miR-17~92 reduce the expression of A20, CYLD and Rnf11 in ABC-DLBCL cells. Figure 2. miR-17~92 directly regulates A20, CYLD and Rnf11 in ABC-DLBCL cells. (A) Fluorescence images of tranduced ABC-DLBCL cells. (B) Expression of sponge or miR-17~92 in tranduced ABC-DLBCL cells. (C) Inhibition of miR-17~92 increase the expression of A20, CYLD and Rnf11. Overexpression of miR-17~92 reduce the expression of A20, CYLD and Rnf11 in ABC-DLBCL cells. Figure 3. miR-17~92 modulate mediate NF-kB activity in ABC-DLBCL. (A) Immunoblot analysis of IkB-a, NF-kB p65, NF-kB p100/p52 and their phosphorylation. (B) Heat-map display of quantitative real-time RT-PCR measurements of six independent NF-kB transcriptional targets show significantly lower expression in sponge expressing cells and higher expression in miR-17~92 expressing cells. Figure 3. miR-17~92 modulate mediate NF-kB activity in ABC-DLBCL. (A) Immunoblot analysis of IkB-a, NF-kB p65, NF-kB p100/p52 and their phosphorylation. (B) Heat-map display of quantitative real-time RT-PCR measurements of six independent NF-kB transcriptional targets show significantly lower expression in sponge expressing cells and higher expression in miR-17~92 expressing cells. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 5118 Mantle cell lymphoma (MCL) is an aggressive hematological malignancy with a median survival ranging between 3 and 5 years. Novel therapeutic strategies are urgently needed to improve the outcome. Mammalian target of rapamycin (mTOR) pathway which plays a central role in controlling cell growth, proliferation and metabolism has been shown to be deregulated in MCL. mTOR inhibitors, such as rapamycin and its analogues, have been approved for treatment of relapsed/refractory MCL. However, the molecular mechanism of mTOR activation in MCL has yet to be defined. MiRNA (miR)-17∼92 is a cluster of six miRNAs which are frequently overexpressed in MCL cases and overexpression of the miR-17∼92 cluster in MCL predicts poor prognosis. Our previous study demonstrated that miR-17∼92 activated the PI3K/AKT pathway by directly targeting PTEN and PHLPP2; and knock-down of miR-17∼92 expression inhibited MCL tumor growth in a xenograft/SCID MCL mouse model. In the present study, we further demonstrated that knock-down miR-17∼92 decreased the cell size, similar effect as seen in cells treated with mTORC1 inhibitors. Knockdown of miR-17∼92 expression also decreased the glycolysis, protein synthesis and glucose uptake in MCL cells. We found that knockdown miR-17∼92 activated AMPK signaling as demonstrated by increased phosphorylation of AMPK at Thr172, especially under low glucose condition. Activated AMPK further phosphorylated TSC2 and Raptor at S1387 and S792, respectively, thereby inhibiting mTORC1 signaling as evidenced by decreased phosphorylation of RPS6 and 4E-BP1. Using TargetScan and other prediction algorithms, we found that several factors in the LKB1/AMPK/mTOR pathway, such as LKB1, CAB39, PRKAA1 and TSC1, are predicted the targets of miR-17∼92. In this study, we validated these factors as direct targets of the miR-17∼92 by 3'UTR luciferase assays using reporter plasmids containing the 3'UTR of the targets or the 3'UTR with mutations in the predicted miRNA binding sites. The protein levels of these targets decreased in MCL cells with the miR-17∼92 overexpression. Conversely, the levels of these factors were increased upon knockdown of miR-17∼92 cluster. Our results indicate that overexpression of miR-17∼92 in MCL plays important role in mTORC1 activation by inactivating the LKB1/AMPK signaling, in addition to its effect on the PI3K/AKT pathway activation. Disclosures: No relevant conflicts of interest to declare.