Loss of AXIN1 drives acquired resistance to
            <scp>WNT</scp>
            pathway blockade in colorectal cancer cells carrying
            <scp>RSPO</scp>
            3 fusions

Picco, Gabriele; Petti, Consalvo; Centonze, Alessia; Torchiaro, Erica; Crisafulli, Giovanni; Novara, Luca; Acquaviva, Andrea; Bardelli, Alberto; Medico, Enzo

doi:10.15252/emmm.201606773

Cited by 60 publications

(31 citation statements)

References 52 publications

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“…A potential strategy to trigger the β-catenin pathway is inhibition of Axin1. Picco et al showed that targeting Axin1 with the porcupine inhibitor LGK974 was a potential approach for the treatment of colorectal cancer (Picco et al, 2017). Chimge and colleagues reported that RUNX1-mediated Axin1 suppression led to the activation of β-catenin (Chimge et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

TRIM65 triggers β-catenin signaling via ubiquitylation of Axin1 to promote hepatocellular carcinoma

Yang

Zhang

Qing

et al. 2017

Journal of Cell Science

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Deregulation of ubiquitin ligases contributes to the malignant progression of human cancers. Tripartite motif-containing protein 65 (TRIM65) is an E3 ubiquitin ligase and has been implicated in human diseases, but its role and clinical significance in hepatocellular carcinoma (HCC) remain unknown. Here, we showed that TRIM65 expression was increased in HCC tissues and associated with poor outcome in two independent cohorts containing 888 patients. In vitro and in vivo data demonstrated that overexpression of TRIM65 promoted cell growth and tumor metastasis, whereas knockdown of TRIM65 resulted in opposite phenotypes. Further studies revealed that TRIM65 exerted oncogenic activities via ubiquitylation of Axin1 to activate the β-catenin signaling pathway. TRIM65 directly bound to Axin1 and accelerated its degradation through ubiquitylation. Furthermore, HMGA1 was identified as an upstream regulator of TRIM65 in HCC cells. In clinical samples, TRIM65 expression was positively correlated with the expression of HMGA1 and nuclear β-catenin. Collectively, our data indicate that TRIM65 functions as an oncogene in HCC. The newly identified HMGA1/TRIM65/β-catenin axis serves as a promising prognostic factor and therapeutic target.

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Section: Discussionmentioning

confidence: 99%

TRIM65 triggers β-catenin signaling via ubiquitylation of Axin1 to promote hepatocellular carcinoma

Yang

Zhang

Qing

et al. 2017

Journal of Cell Science

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“…Although clear sensitivity to the Porcupine inhibitor LGK974 was observed in vitro and in vivo in a murine xenograft model, long-term treatment led to the emergence of a resistant population. This resistant population was characterized by two novel frame-shift deletions in AXIN1 , resulting in protein loss [ 143 ]. Although no mutations in Wnt pathway components in MM have been reported, treatment of the active Wnt signaling pathway can thus result in emergence of such mutations.…”

Section: The Wnt Pathway As a Potential Therapeutic Target In Multiplmentioning

confidence: 99%

Wnt signaling in multiple myeloma: a central player in disease with therapeutic potential

et al. 2018

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Multiple myeloma is the second most frequent hematological malignancy in the western world and remains incurable, predominantly due to acquired drug resistance and disease relapse. The highly conserved Wnt signal transduction pathway, which plays a key role in regulating cellular processes of proliferation, differentiation, migration, and stem cell self-renewal, is associated with multiple aspects of disease. Bone homeostasis is severely disturbed by Wnt antagonists that are secreted by the malignant plasma cells in the bone marrow. In the vast majority of patients, this results in osteolytic bone disease, which is associated with bone pain and pathological fractures and was reported to facilitate disease progression. More recently, cumulative evidence also indicates the importance of intrinsic Wnt signaling in the survival of multiple myeloma cells. However, Wnt pathway-activating gene mutations could not be identified. The search for factors or processes responsible for Wnt pathway activation currently focuses on aberrant ligand levels in the bone marrow microenvironment, increased expression of Wnt transcriptional co-factors and associated micro-RNAs, and disturbed epigenetics and post-translational modification processes. Furthermore, Wnt pathway activation is associated with acquired cell adhesion-mediated resistance of multiple myeloma cells to conventional drug therapies, including doxorubicin and lenalidomide. In this review, we present an overview of the relevance of Wnt signaling in multiple myeloma and highlight the Wnt pathway as a potential therapeutic target for this disease.

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“…Anti-tumor activity in RSPO3 fusion containing CRC tumors has been reported with another RSPO3 neutralizing antibody 14 . Two CRC cell lines, VACO6 and SNU1411, have been identified which have PTPRK-RSPO3 fusions, overexpress RSPO3 and are sensitive to porcupine inhibition 20 . The VACO6 xenograft model demonstrates tumor growth inhibition when exposed to anti-RSPO3 alone or in combination with the topoisomerase inhibitor irinotecan or alternatively in combination with nab-paclitaxel (Fig.…”

Section: Introductionmentioning

confidence: 99%

RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations

Fischer

Yeung

Cattaruzza

et al. 2017

Sci Rep

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Activating mutations in the Wnt pathway are a characteristic feature of colorectal cancer (CRC). The R-spondin (RSPO) family is a group of secreted proteins that enhance Wnt signaling and RSPO2 and RSPO3 gene fusions have been reported in CRC. We have previously shown that Wnt pathway blockers exhibit potent combinatorial activity with taxanes to inhibit tumor growth. Here we show that RSPO3 antagonism synergizes with paclitaxel based chemotherapies in patient-derived xenograft models (PDX) with RSPO3 fusions and in tumors with common CRC mutations such as APC, β-catenin, or RNF43. In these latter types of tumors that represent over 90% of CRC, RSPO3 is produced by stromal cells in the tumor microenvironment and the activating mutations appear to sensitize the tumors to Wnt-Rspo synergy. The combination of RSPO3 inhibition and taxane treatment provides an approach to effectively target oncogenic WNT signaling in a significant number of patients with colorectal and other intestinal cancers.

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Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO 3 fusions

Cited by 60 publications

References 52 publications

TRIM65 triggers β-catenin signaling via ubiquitylation of Axin1 to promote hepatocellular carcinoma

TRIM65 triggers β-catenin signaling via ubiquitylation of Axin1 to promote hepatocellular carcinoma

Wnt signaling in multiple myeloma: a central player in disease with therapeutic potential

RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations

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