YAP1 Mediates Resistance to MEK1/2 Inhibition in Neuroblastomas with Hyperactivated RAS Signaling

Coggins, Grace E.; Farrel, Alvin; Rathi, Komal S.; Hayes, Colin M.; Scolaro, Laura; Rokita, Jo Lynne; Maris, John M.

doi:10.1158/0008-5472.can-19-1415

Cited by 53 publications

(47 citation statements)

References 57 publications

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“…For example, YAP/TAZ inactivation may cause compensatory lysosome-mediated activation of MAPK signaling in NF2 tumor growth ( 39 ). Additionally, YAP may also mediate resistance to MEK1/2 inhibition in neuroblastomas with hyperactivated RAS signaling ( 40 ). These studies suggest that targeting of both YAP/TAZ and MAPK signaling may provide additive or synergistic therapeutic benefit.…”

Section: Resultsmentioning

confidence: 99%

Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling

Chen¹,

Li²,

Mao³

et al. 2020

JCI Insight

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Schwannomas are tumors of the Schwann cells that cause chronic pain, numbness, and potentially life-threatening impairment of vital organs. Despite the identification of causative genes, including NF2 (Merlin), INI1/SMARCB1, and LZTR1, the exact molecular mechanism of schwannoma development is still poorly understood. Several studies have identified Merlin as a key regulator of the Hippo, MAPK, and PI3K signaling pathways; however, definitive evidence demonstrating the importance of these pathways in schwannoma pathogenesis is absent. Here, we provide direct genetic evidence that dysregulation of the Hippo pathway in the Schwann cell lineage causes development of multiple schwannomas in mice. We found that canonical Hippo signaling through the effectors YAP/TAZ is required for schwannomagenesis and that MAPK signaling modifies schwannoma formation. Furthermore, cotargeting YAP/TAZ transcriptional activity and MAPK signaling demonstrated a synergistic therapeutic effect on schwannomas. Our new model provides a tractable platform to dissect the molecular mechanisms underpinning schwannoma formation and the role of combinatorial targeted therapy in schwannoma treatment.

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Section: Resultsmentioning

confidence: 99%

Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling

Chen¹,

Li²,

Mao³

et al. 2020

JCI Insight

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“…The MEK inhibitor trametinib is able to inhibit tumor cell growth in neuroblastoma with active ERK functions, suggesting a therapeutic treatment option for neuroblastoma patients [ 78 ]. However, extending trametinib use in neuroblastoma is challenged by the fact that constitutively active YAP overexpression induces resistance against trametinib in MAPK pathway-activated neuroblastoma cells via transcriptional activation of E2F and MYCN [ 79 ]. Conversely, loss of YAP sensitizes neuroblastoma cells to trametinib, implying that combinatorial inhibition of MEK and YAP signaling could be a therapeutic strategy for neuroblastoma patients with hyperactivated MAPK signaling.…”

Section: Hippo Signaling Pathway-mediated Drug Resistancementioning

confidence: 99%

The Hippo Signaling Pathway in Drug Resistance in Cancer

Zeng

Dong

2021

Cancers

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Chemotherapy represents one of the most efficacious strategies to treat cancer patients, bringing advantageous changes at least temporarily even to those patients with incurable malignancies. However, most patients respond poorly after a certain number of cycles of treatment due to the development of drug resistance. Resistance to drugs administrated to cancer patients greatly limits the benefits that patients can achieve and continues to be a severe clinical difficulty. Among the mechanisms which have been uncovered to mediate anti-cancer drug resistance, the Hippo signaling pathway is gaining increasing attention due to the remarkable oncogenic activities of its components (for example, YAP and TAZ) and their druggable properties. This review will highlight current understanding of how the Hippo signaling pathway regulates anti-cancer drug resistance in tumor cells, and currently available pharmacological interventions targeting the Hippo pathway to eradicate malignant cells and potentially treat cancer patients.

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“…YAP1 is the downstream effector of the Hippo signaling pathway, and in cooperation with the TEA domain transcription factor 1, increased YAP1 expression stimulates a number of target genes responsible for cell viability and apoptosis (20,21). Several studies have demonstrated that increased YAP1 expression is associated with elevated drug resistance in numerous cancer cells, such as neuroblastoma, esophageal cancer and colorectal cancer cells (22)(23)(24)(25). The present study investigated the mechanism of the synergistic effects of YAP1 with cisplatin.…”

Section: Discussionmentioning

confidence: 96%

Atorvastatin potentiates the chemosensitivity of human liver cancer cells to cisplatin via downregulating YAP1

et al. 2020

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Atorvastatin is a competitive inhibitor of β-hydroxy β-methylglutaryl-CoA reductase, which is involved in anticancer effects in numerous types of cancer, including in human liver cancer. However, its functions and underlying mechanisms of chemosensitivity in liver cancer remain to be elucidated. The present study investigated the effect of atorvastatin on cisplatin chemosensitivity and its molecular mechanisms, with a focus on the Yes1-associated transcriptional regulator (YAP1) protein. The present study demonstrated that atorvastatin significantly potentiated chemosensitivity to cisplatin in the liver cancer HepG2 and Huh-7 cell lines. Furthermore, cell survival and apoptosis in liver cancer cell lines were analyzed using MTT assay and flow cytometry, respectively. Atorvastatin suppressed HepG2 and Huh-7 cell viability in a dose-dependent manner, similar to cisplatin and paclitaxel. Subtoxic levels of atorvastatin significantly increased cisplatin-induced apoptosis in Huh-7 cells. Atorvastatin-promoted chemosensitivity was predominantly mediated by caspase 3, caspase 9 and poly-(ADP ribose)-polymerase activation, and YAP1 downregulation. Finally, YAP1 overexpression significantly reversed the susceptibility of Huh-7 cells to cisplatin. Overall, the results of the present study suggested the underlying mechanisms of atorvastatin chemosensitivity in inducing liver cancer cell apoptosis via downregulating YAP1 and implicated the potential application of atorvastatin-potentiated chemosensitivity in liver cancer therapy.

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YAP1 Mediates Resistance to MEK1/2 Inhibition in Neuroblastomas with Hyperactivated RAS Signaling

Cited by 53 publications

References 57 publications

Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling

Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling

The Hippo Signaling Pathway in Drug Resistance in Cancer

Atorvastatin potentiates the chemosensitivity of human liver cancer cells to cisplatin via downregulating YAP1

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