A brief review: some compounds targeting YAP against malignancies

Tang, Zhenxue; Ma, Qingxia; Wang, Luyao; Liu, Chaolong; Gao, Hui; Yang, Zhihong; Liu, Zhantao; Zhang, Huimin; Ji, Lixia; Jiang, Guohui

doi:10.2217/fon-2019-0035

Cited by 21 publications

(13 citation statements)

References 52 publications

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“…It follows that therapies targeting YAP may potentially enhance the efficacy of anti-PD-1/PD-L1 ICIs in EGFR-mutant NSCLC. A few small molecule compounds or drugs, including dasatinib, JQ1, norcantharidin, MLN8237 and dobutamine, have been shown to inhibit YAP ( 150 ). Further investigation is needed to verify the beneficial effect of combining YAP inhibitors with anti-PD-1/PD-L1 ICIs for treating EGFR TKI resistant NSCLC.…”

Section: Novel Strategies To Potentiate Pd-1/pd-l1 Blockade Immunotherapy In Egfr Mutant Nsclcmentioning

confidence: 99%

Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies

Fong

Cho

2021

Front. Oncol.

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Lung cancer is the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors, including monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), have dramatically improved the survival and quality of life of a subset of non-small cell lung cancer (NSCLC) patients. Multiple predictive biomarkers have been proposed to select the patients who may benefit from the immune checkpoint inhibitors. EGFR-mutant NSCLC is the most prevalent molecular subtype in Asian lung cancer patients. However, patients with EGFR-mutant NSCLC show poor response to anti-PD-1/PD-L1 treatment. While small-molecule EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for EGFR-mutant NSCLC, acquired drug resistance is severely limiting the long-term efficacy. However, there is currently no further effective treatment option for TKIs-refractory EGFR-mutant NSCLC patients. The reasons mediating the poor response of EGFR-mutated NSCLC patients to immunotherapy are not clear. Initial investigations revealed that EGFR-mutated NSCLC has lower PD-L1 expression and a low tumor mutational burden, thus leading to weak immunogenicity. Moreover, the use of PD-1/PD-L1 blockade prior to or concurrent with osimertinib has been reported to increase the risk of pulmonary toxicity. Furthermore, emerging evidence shows that PD-1/PD-L1 blockade in NSCLC patients can lead to hyperprogressive disease associated with dismal prognosis. However, it is difficult to predict the treatment toxicity. New biomarkers are urgently needed to predict response and toxicity associated with the use of PD-1/PD-L1 immunotherapy in EGFR-mutated NSCLC. Recently, promising data have emerged to suggest the potentiation of PD-1/PD-L1 blockade therapy by anti-angiogenic agents and a few other novel therapeutic agents. This article reviews the current investigations about the poor response of EGFR-mutated NSCLC to anti-PD-1/PD-L1 therapy, and discusses the new strategies that may be adopted in the future.

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Section: Novel Strategies To Potentiate Pd-1/pd-l1 Blockade Immunotherapy In Egfr Mutant Nsclcmentioning

confidence: 99%

Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies

Fong

Cho

2021

Front. Oncol.

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“…[107,108,109,110,111,112]. Small molecule inhibitors or drugs have been discovered that inhibit YAP, including dasatinib, statins, A35, JQ1, norcantharidin, agave, MLN8237, and dobutamine [135]. More in vitro and in vivo experiments are warranted to investigate the efficacy of YAP inhibition in combination with anti-PD-L1/PD-1 ICIs for EGFR-TKI resistant NSCLC.…”

Section: Future Perspectivesmentioning

confidence: 99%

Epidermal Growth Factor Receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the Regulation of Programmed Death-Ligand 1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC)

Hsu

Jablons

Yang

et al. 2019

IJMS

137

100

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The epidermal growth factor receptor (EGFR) pathway is a well-studied oncogenic pathway in human non-small cell lung cancer (NSCLC). A subset of advanced NSCLC patients (15–55%) have EGFR-driven mutations and benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) targeting the PD-1/PDL-1 axis are a new anti-cancer therapy for metastatic NSCLC. The anti-PD-1/PDL-1 ICIs showed promising efficacy (~30% response rate) and improved the survival of patients with metastatic NSCLC, but the role of anti-PD-1/PDL-1 ICIs for EGFR mutant NSCLC is not clear. YAP (yes-associated protein) is the main mediator of the Hippo pathway and has been identified as promoting cancer progression, drug resistance, and metastasis in NSCLC. Here, we review recent studies that examined the correlation between the EGFR, YAP pathways, and PD-L1 and demonstrate the mechanism by which EGFR and YAP regulate PD-L1 expression in human NSCLC. About 50% of EGFR mutant NSCLC patients acquire resistance to EGFR-TKIs without known targetable secondary mutations. Targeting YAP therapy is suggested as a potential treatment for NSCLC with acquired resistance to EGFR-TKIs. Future work should focus on the efficacy of YAP inhibitors in combination with immune checkpoint PD-L1/PD-1 blockade in EGFR mutant NSCLC without targetable resistant mutations.

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“…Verteporfin, an inhibitor of YAP1, has been widely used to study the Hippo-YAP1/TAZ pathway (Khalafalla et al, 2017;Ikeda et al, 2019b). Verteporfin combined with YAP1 prevents the interaction of the YAP1-TEADs complex; verteporfin alters the conformation of YAP1 to enhance its binding with trypsin as well as tryptic cleavage (Liu-Chittenden et al, 2012;Tang et al, 2019). As mentioned in Section "Role of Hippo-YAP1/TAZ Signaling and Its Differentiation Output in Heart Development, " YAP1/TEAD1-OSM feedback cycle exacerbates heart failure and the progression of diabetic cardiomyopathy in HFD-fed mice following TAC (Ikeda et al, 2019b).…”

Section: Compounds That Regulate Hippo-yap1/taz Signalingmentioning

confidence: 99%

Molecular Mechanism of Hippo–YAP1/TAZ Pathway in Heart Development, Disease, and Regeneration

Chen

Luo

et al. 2020

Front. Physiol.

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The Hippo-YAP1/TAZ pathway is a highly conserved central mechanism that controls organ size through the regulation of cell proliferation and other physical attributes of cells. The transcriptional factors Yes-associated protein 1 (YAP1) and PDZ-binding motif (TAZ) act as downstream effectors of the Hippo pathway, and their subcellular location and transcriptional activities are affected by multiple post-translational modifications (PTMs). Studies have conclusively demonstrated a pivotal role of the Hippo-YAP1/TAZ pathway in cardiac development, disease, and regeneration. Targeted therapeutics for the YAP1/TAZ could be an effective treatment option for cardiac regeneration and disease. This review article provides an overview of the Hippo-YAP1/TAZ pathway and the increasing impact of PTMs in fine-tuning YAP1/TAZ activation; in addition, we discuss the potential contributions of the Hippo-YAP1/TAZ pathway in cardiac development, disease, and regeneration.

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A brief review: some compounds targeting YAP against malignancies

Cited by 21 publications

References 52 publications

Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies

Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies

Epidermal Growth Factor Receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the Regulation of Programmed Death-Ligand 1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC)

Molecular Mechanism of Hippo–YAP1/TAZ Pathway in Heart Development, Disease, and Regeneration

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