Targeted Disruption of the BCL9/β-Catenin Complex Inhibits Oncogenic Wnt Signaling

Takada, Kohichi; Zhu, Di; Bird, Gregory H.; Sukhdeo, Kumar; Zhao, Jianjun; Mani, Mala; Lemieux, Madeleine E.; Carrasco, Daniel E.; Ryan, Jeremy; Horst, David; Fulciniti, Mariateresa; Munshi, Nikhil C.; Xu, Wenqing; Kung, Andrew L.; Shivdasani, Ramesh A.; Walensky, Loren D.; Carrasco, Daniel R.

doi:10.1126/scitranslmed.3003808

Cited by 228 publications

(268 citation statements)

References 57 publications

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“…Downstream inhibition of Wnt/β-catenin signaling by a dominant negative form of TCF4 (dnTCF4) and shRNA-mediated silencing of β-catenin, BCL9-like peptides, or small-molecule Wnt inhibitors has been previously shown to impair MM proliferation and expansion (6,7,9,35). To confirm and extend these data, we expressed dnTCF4 in the HMCLs LME-1, RIES, and XG-1 from a bicistronic vector containing a fluorescent marker.…”

Section: R-spondins Potentiate Wnt Signaling In MM In a Lgr4-dependentmentioning

confidence: 99%

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Andel

Ren

Koopmans

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche. Here, we report a pivotal role for the R-spondin/leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) axis in driving aberrant Wnt/ β-catenin signaling in MM. We show that LGR4 is expressed by MM plasma cells, but not by normal plasma cells or B cells. This aberrant LGR4 expression is driven by IL-6/STAT3 signaling and allows MM cells to hijack R-spondins produced by (pre)osteoblasts in the BM niche, resulting in Wnt (co)receptor stabilization and a dramatically increased sensitivity to auto-and paracrine Wnts. Our study identifies aberrant R-spondin/LGR4 signaling with consequent deregulation of Wnt (co)receptor turnover as a driver of oncogenic Wnt/ β-catenin signaling in MM cells. These results advocate targeting of the LGR4/R-spondin interaction as a therapeutic strategy in MM.M ultiple myeloma (MM) in most patients is an incurable hematologic malignancy characterized by the accumulation of clonal plasma cells in the bone marrow (BM). Despite the wide variety of underlying structural and numerical genomic abnormalities (1-3), virtually all MMs are highly dependent on a protective BM microenvironment, or "niche," for growth and survival (4). Understanding the complex reciprocal interaction between MM cells and the BM microenvironment is critical for the development of new targeted therapies.In MM, aberrant activation of the canonical Wnt pathway drives proliferation and is associated with disease progression, dissemination, and drug resistance (5-9). Because MMs with hallmarks of active Wnt signaling do not harbor mutations that typically underlie constitutive Wnt pathway activation, this oncogenic Wnt pathway activity was proposed to involve autocrine and/or paracrine Wnt ligands (6,8,10). Wnts are lipid-modified glycoproteins that function as typical niche factors because they are relatively unstable and insoluble due to their hydrophobic nature, which constrains long-range signaling (11). Binding of a Wnt ligand to its receptor Frizzled (Fzd) initiates a signaling cascade that ultimately results in stabilization and nuclear translocation of the Wnt effector β-catenin. In cooperation with TCF/LEF family transcription factors this orchestrates a transcriptional program (12, 13), comprising targets such as MYC and CCND1 (Cyclin D1) that play crucial roles in the pathogenesis of MM (14-16). Aberrant Wnt signaling in cancer typically results from mutations in APC, β-catenin (CTNNB1), or AXIN that drive constitutive, ligand-independent pathway ac...

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Section: R-spondins Potentiate Wnt Signaling In MM In a Lgr4-dependentmentioning

confidence: 99%

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Andel

Ren

Koopmans

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, HIF3A, inhibitor of HIF-mediated gene expression was also found to be hypermethylated in our study consistent with a recent report. 40 Wnt signaling pathway was affected by both hypomethylation of Bcl9, a Wnt activator 41 and hypermethylation of Wnt suppressors, such as, SOX17, APC, SFRP2, SFRP5, and DKK3. 42 Epigenetic alteration has been previously described in SOX17, APC, SFRP2, SFRP5, and DKK3 in human cancers and may result in deregulated Wnt signaling (primary references available at http://www.stanford.edu/group/nusselab/cgi-bin/wnt/).…”

Section: Tlx3 and Pax3 We Found Promoter Hypermethylation Inmentioning

confidence: 99%

Whole genome DNA methylation signature of HER2-positive breast cancer

et al. 2014

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“…By sampling alternative staple positions, interrogating cellular uptake, and correlating biochemical function with antitumor activity and mechanism of action, we have generated lead compounds that form the basis for therapeutic development (16,17,19,20). Here, we report the application of all-hydrocarbon stapling to recapitulate the native primary sequence and secondary structure of the RAS-interacting α-helix of SOS1.…”

mentioning

confidence: 99%

“…We have previously generated "stapled peptides" modeled after key α-helical interaction domains to disrupt oncogenic protein interactions of the BCL-2 family, p53, β-catenin, and EZH2 pathways (15)(16)(17)(18). By sampling alternative staple positions, interrogating cellular uptake, and correlating biochemical function with antitumor activity and mechanism of action, we have generated lead compounds that form the basis for therapeutic development (16,17,19,20).…”

mentioning

confidence: 99%

Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices

Leshchiner

Parkhitko²,

Bird

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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148

121

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Activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) underlie the pathogenesis and chemoresistance of ∼30% of all human tumors, yet the development of high-affinity inhibitors that target the broad range of KRAS mutants remains a formidable challenge. Here, we report the development and validation of stabilized alpha helices of son of sevenless 1 (SAH-SOS1) as prototype therapeutics that directly inhibit wild-type and mutant forms of KRAS. SAH-SOS1 peptides bound in a sequence-specific manner to KRAS and its mutants, and dose-responsively blocked nucleotide association. Importantly, this functional binding activity correlated with SAH-SOS1 cytotoxicity in cancer cells expressing wild-type or mutant forms of KRAS. The mechanism of action of SAH-SOS1 peptides was demonstrated by sequencespecific down-regulation of the ERK-MAP kinase phosphosignaling cascade in KRAS-driven cancer cells and in a Drosophila melanogaster model of Ras85D V12 activation. These studies provide evidence for the potential utility of SAH-SOS1 peptides in neutralizing oncogenic KRAS in human cancer.R AS signaling is a critical control point for a host of cellular functions ranging from cellular survival and proliferation to cellular endocytosis and motility (1). The on or off state of RAS is dictated by nucleotide exchange. GTP-bound RAS is the activated form that engages its downstream effectors with high avidity. The endogenous GTPase activity of RAS hydrolyzes GTP to GDP and inactivates signaling. This biochemical process is further regulated by GTPase-activating proteins (GAPs) that impair RAS signaling through increasing endogenous GTPase activity and guanine-nucleotide exchange factors (GEFs) that enhance RAS signaling by facilitating GDP release and, thus, GTP association. Given the central roles of RAS in cellular growth and metabolism, it is not surprising that cancer cells usurp its prosurvival activities to achieve immortality.Activating mutations in KRAS represent the most frequent oncogenic driving force among the RAS homologs K-, N-, and H-RAS, and are associated with poor prognosis and chemoresistance (2). KRAS mutations are present in ∼30% of human tumors and at even higher frequencies in cancers of the pancreas, lung, thyroid gland, colon, and liver. For example, in pancreatic ductal adenocarcinomas (PDAC) that carry a 5-y survival rate of less than 5%, activating KRAS mutations are present in more than 90% of tumors (3). Thus, therapeutic inhibition of RAS is among the highest priority goals of the cancer field. Because oncogenic forms of KRAS typically harbor single-point mutants that stabilize its active GTP-bound form, a host of recent small molecule and peptide development efforts have been aimed at disarming this pathologic biochemical state. The extremely high affinity of KRAS for its GTP substrate has hampered the development of competitive GTP inhibitors. However, a GDP mimetic that covalently modifies the mutant cysteine of KRAS G12C represents a promising approach to plugging the nucleotid...

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Targeted Disruption of the BCL9/β-Catenin Complex Inhibits Oncogenic Wnt Signaling

Cited by 228 publications

References 57 publications

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Whole genome DNA methylation signature of HER2-positive breast cancer

Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices

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