Epigenetic Targeting of Mcl-1 is Synthetically Lethal with Bcl-xL/Bcl-2 Inhibition in Model Systems of Glioblastoma
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PROVIDER: PRJNA634319 | ENA |
REPOSITORIES: ENA
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Project description:Glioblastomas harbor a super-enhancer at the MCL1 locus, which translates to increased MCL1 levels as compared to normal brain tissue. While suppression of Mcl-1 alone did not yield in significant apoptosis induction, combined inhibition of Bcl-xL/Bcl-2 along with Mcl-1 led to strong cell killing and reduction of tumor growth in patient-derived xenograft models in vivo.
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Project description:The heterogeneous therapy response observed in colorectal cancer is in part due to cancer stem cells (CSCs) that resist chemotherapeutic insults. The anti-apoptotic protein BCL-XL plays a critical role in protecting CSCs from cell death, where its inhibition with high doses of BH3-mimetics can induce apoptosis. To identify pathways that can regulate sensitivity to BCL-XL inhibition, we screened a compound library for synergy with low dose BCL-XL inhibitor A-1155463 and reveal that FGFR4 inhibition effectively sensitizes to A-1155463 both in vitro and in vivo. Mechanistically, we identify a rescue response that is activated upon BCL-XL inhibition and leads to rapid FGF2 secretion and subsequent FGFR4-mediated post-translational stabilization of MCL-1. FGFR4 inhibition prevents MCL-1 upregulation and thereby sensitizes CSCs to BCL-XL inhibition. Altogether, our findings suggest a cell transferable induction of a FGF2/FGFR4 rescue response in CRC that is induced upon BCL-XL inhibition and leads to MCL-1 upregulation.
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Project description:Glioblastoma (GBM) remains an incurable disease, requiring more effective therapies. Through CRISPR and RNAi library screening interrogation we identified several TCA-cycle enzymes as essential for GBM growth. By combining a transcriptome and metabolite screening analyses we discovered that loss of function of OGDH by the clinically validated drug compound, CPI-613, is synthetically lethal with Bcl-xL inhibition (genetically and through the clinically validated BH3-mimetic, ABT263) in patient-derived xenograft as well neurosphere GBM cultures. CPI-613 mediated energy deprivation drives an integrated stress response with an up-regulation of the BH3-only domain protein, Noxa in an ATF4 dependent manner as demonstrated by genetic loss of function experiments. Consistently, silencing of Noxa rescued from cell death induced by CPI-613 in model systems of GBM. In patient-derived xenograft models of GBM in mice, the combination treatment of ABT263 and CPI613 suppressed tumor growth more potently than each compound on its own. Therefore, combined inhibition of Bcl-xL along with interference of the TCA-cycle might be a novel treatment strategy for GBM.
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Project description:Bcl-xL is an anti-apoptotic protein that is frequently found to be overexpressed in non-small cell lung cancer leading to an inhibition of apoptosis and poor prognosis. Recently, the role of miRNAs in regulating apoptosis and cell survival during tumorigenesis has become evident, with cancer cells showing perturbed expression of various miRNAs. We utilized miRNA microarrays to determine if miRNA dysregulation in bcl-xL silenced lung adenocarcinoma cells could be involved in regulating apoptotic behavior, and identified dysregulated miRNAs with putative targets involved in signal transduction pathways regulating apoptosis, cell proliferation and cell progression. Short interfering RNA-based transfection of A549 was carried out inducing a reduction in bcl-xL expression levels. 24 hours post-transfection total RNA was isolated using TRIzol reagent and hybridized onto Affymetrix GeneChip miRNA Arrays. A global miRNA expression profile was then established, which compared total RNA, extracted from siRNA-transfected and non-transfected A549 cells. All experiments were carried out with three independent biological replicates.
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Project description:By integration of transcriptome and metabolite analyses, we showed that pharmacological activation of the mitochondrial ClpP protease through utilization of enhanced imipridone compounds (ONC206 and ONC212) in combination with global (Panobinostat) and selective (romidepsin) HDAC – inhibitors caused synergistic reduction of viability in established and patient-derived xenograft (PDX) cultures of human GBM. This effect occurred independent of TP53 status and was partially mediated by activation of a cell death with apoptotic features accompanied by activation of initiator and effector caspases as well as cleavage of PARP. Consistently, the combination treatment altered the expression of anti-apoptotic and pro-apoptotic Bcl-2 family members, resulting in down-regulation of Bcl-xL and Mcl-1. Knockdown experiments targeting Noxa, BIM, Bcl-xL and Mcl-1 confirmed a functional implication of these proteins in the reduction of cellular viability mediated by the combination treatment. Importantly, knockdown of the ClpP protease significantly rescued the reduction of cellular viability by ClpP activators and the combination treatment, respectively, suggesting critical involvement of this protein. We used microarrays to detail the global programme of gene expression underlying cellularization and identified distinct classes of up-regulated and down-regulated genes in cells treated with ONC206 and Romidepsin.
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Project description:Genome-wide genetic screens have identified cellular dependencies in many cancers. Using Novartis’ DRIVE and the Broad Institute’s Achilles shRNA screening datasets, we mined for targetable dependencies in kidney lineage cancer cells. Our studies identified a dependency, preferentially in kidney cancer cells versus cells of other lineages, on the BCL2L1 gene, which encodes the Bcl-xL anti-apoptotic protein. Genetic and pharmacological inactivation of Bcl-xL, but not its paralog BCL2, led to fitness defects in renal cancer cells, and also sensitized them to chemotherapeutics. Expression levels of Bcl-xL, VHL status, and p53 mutation status were insufficient to predict Bcl-xL dependence. Instead, analyzing the transcriptional hallmarks of response to Bcl-xL blockade identified an elevated mesenchymal cell state signature in Bcl-xL dependent lines. Functional studies to address if these cell state differences drive Bcl-xL dependence showed that maintaining mesenchymal characteristics was necessary to confer sensitivity to Bcl-xL loss; and, conversely, that promoting mesenchymal transition was sufficient to increase sensitivity to Bcl-xL inhibition in resistant cells. This mesenchymal signature was also observed in almost a third of human renal tumors, and is associated with worse clinical outcomes. Detachment from an organized epithelium incites protective apoptotic responses in normal cells (e.g. anoikis); however, our findings suggest that, in mesenchymal kidney cancer cells Bcl-xL activity counteracts this protective mechanism and enables tumor cell survival. Altogether, our studies uncover an unexpected link between cellular cell state and dependence on anti-apoptotic proteins, and justify the use of Bcl-xL blockade to target a clinically aggressive subset of human kidney cancers.
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Project description:The anti-apoptotic function of Bcl-xL in the heart against reperfusion injury is diminished by K-Ras-Mst1-mediated phosphorylation of Ser14, which allows dissociation of Bcl-xL from Bax and promotes cardiomyocyte death. Here we show that Ser14 phosphorylation of Bcl-xL is also promoted by hemodynamic stress in the heart, through the H-Ras-ERK pathway. Our study suggests that phosphorylation of Bcl-xL at Ser14 in response to acute pressure overload plays an essential role in mediating compensatory hypertrophy by promoting calcium release, alleviating the negative constraint of Bcl-xL upon the IP3R-NFAT pathway.
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Project description:Bcl-xL is an anti-apoptotic protein that is frequently found to be overexpressed in non-small cell lung cancer leading to an inhibition of apoptosis and poor prognosis. Recently, the role of miRNAs in regulating apoptosis and cell survival during tumorigenesis has become evident, with cancer cells showing perturbed expression of various miRNAs. We utilized miRNA microarrays to determine if miRNA dysregulation in bcl-xL silenced lung adenocarcinoma cells could be involved in regulating apoptotic behavior, and identified dysregulated miRNAs with putative targets involved in signal transduction pathways regulating apoptosis, cell proliferation and cell progression.
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