Ibrutinib Blocks YAP1 Activation and Reverses BRAF Inhibitor Resistance in Melanoma Cells

Misek, Sean A.; Newbury, Patrick; Chekalin, Evgenii; Paithankar, Shreya; Doseff, Andrea I.; Chen, Bin; Gallo, Kathleen A.; Neubig, Richard R.

doi:10.1124/molpharm.121.000331

Cited by 8 publications

(6 citation statements)

References 69 publications

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“…5 A ) and increased Hippo pathway-mediated YAP S127 and TAZ S89 phosphorylation ( Fig. 5 B ), confirming the previous report showing that ibrutinib inhibits YAP activity in melanoma cells ( 42 ). Of note , NOKs do not express the BTK protein ( SI Appendix , Fig.…”

Section: Resultssupporting

confidence: 88%

“…Given our findings that activation of YAP and TAZ is essential for the ability of EBV infection to enhance proliferation, inhibit differentiation and induce the EMT phenotype in NOKs, we next examined whether treating EBV-infected NOKs with the FDA-approved drugs, Ibrutinib or dasatinib, reduces EBV-induced activation of YAP and/or TAZ, and/or reverses any of the EBV-mediated phenotypes in NOKs. Ibrutinib was chosen for study since this first-generation BTK inhibitor (which is used to treat B cell malignancies such as CLL) was recently shown to prevent YAP nuclear localization via an off-target effect ( 42 ), and has also been reported to inhibit Src kinase activity via an off-target effect ( 43 ). Dasatinib (which is used to treat a number of different malignancies) was chosen for study because it inhibits Src kinase activity through its on-target effect ( 44 ), and EBV infection promotes Src-kinase mediated YAP Y357 phosphorylation in NOKs.…”

Section: Resultsmentioning

confidence: 99%

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Epstein–Barr virus LMP1 protein promotes proliferation and inhibits differentiation of epithelial cells via activation of YAP and TAZ

Singh

Nelson

Pawelski

et al. 2023

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

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Latent Epstein–Barr virus (EBV) infection promotes undifferentiated nasopharyngeal carcinomas (NPCs) in humans, but the mechanism(s) for this effect has been difficult to study because EBV cannot transform normal epithelial cells in vitro and the EBV genome is often lost when NPC cells are grown in culture. Here we show that the latent EBV protein, LMP1 (Latent membrane protein 1), induces cellular proliferation and inhibits spontaneous differentiation of telomerase-immortalized normal oral keratinocytes (NOKs) in growth factor-deficient conditions by increasing the activity of the Hippo pathway effectors, YAP (Yes-associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif). We demonstrate that LMP1 enhances YAP and TAZ activity in NOKs both by decreasing Hippo pathway-mediated serine phosphorylation of YAP and TAZ and increasing Src kinase-mediated Y357 phosphorylation of YAP. Furthermore, knockdown of YAP and TAZ is sufficient to reduce proliferation and promote differentiation in EBV-infected NOKs. We find that YAP and TAZ are also required for LMP1-induced epithelial-to-mesenchymal transition. Importantly, we demonstrate that ibrutinib (an FDA-approved BTK inhibitor that blocks YAP and TAZ activity through an off-target effect) restores spontaneous differentiation and inhibits proliferation of EBV-infected NOKs at clinically relevant doses. These results suggest that LMP1-induced YAP and TAZ activity contributes to the development of NPC.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Epstein–Barr virus LMP1 protein promotes proliferation and inhibits differentiation of epithelial cells via activation of YAP and TAZ

Singh

Nelson

Pawelski

et al. 2023

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

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“…The Library of Integrated Cellular Signatures (LINCS) database, including gene expression profiles for compound-treated cells, has been extensively used for drug prediction in a wide range of diseases including Alzheimer’s [ 56 ] and melanoma [ 35 ], in which the relevant cell lines are not even included in LINCS [ 35 ]. The library comprises 476,251 signatures and 22,268 genes including 978 landmark genes.…”

Section: Methodsmentioning

confidence: 99%

Reversal of cancer gene expression identifies repurposed drugs for diffuse intrinsic pontine glioma

Zhao

Newbury

Ishi

et al. 2022

acta neuropathol commun

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Diffuse intrinsic pontine glioma (DIPG) is an aggressive incurable brainstem tumor that targets young children. Complete resection is not possible, and chemotherapy and radiotherapy are currently only palliative. This study aimed to identify potential therapeutic agents using a computational pipeline to perform an in silico screen for novel drugs. We then tested the identified drugs against a panel of patient-derived DIPG cell lines. Using a systematic computational approach with publicly available databases of gene signature in DIPG patients and cancer cell lines treated with a library of clinically available drugs, we identified drug hits with the ability to reverse a DIPG gene signature to one that matches normal tissue background. The biological and molecular effects of drug treatment was analyzed by cell viability assay and RNA sequence. In vivo DIPG mouse model survival studies were also conducted. As a result, two of three identified drugs showed potency against the DIPG cell lines Triptolide and mycophenolate mofetil (MMF) demonstrated significant inhibition of cell viability in DIPG cell lines. Guanosine rescued reduced cell viability induced by MMF. In vivo, MMF treatment significantly inhibited tumor growth in subcutaneous xenograft mice models. In conclusion, we identified clinically available drugs with the ability to reverse DIPG gene signatures and anti-DIPG activity in vitro and in vivo. This novel approach can repurpose drugs and significantly decrease the cost and time normally required in drug discovery.

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“…Here, several lines of evidence support this possibility. On one hand, ibrutinib has been investigated for resensitizing BRAF-inhibitor refractory melanomas( 60 ), a benefit not replicated with other BTK inhibitors indicative of ibrutinib-specific BRAF effects. Additionally, CORUM over-representation results indicated that ibrutinib treatment may interrupt BRAF interaction with MEK proteins (Figure 2A, Supplementary Figure 7), and experimental structure of the BRAF kinase domain in complex with MEK( 61 ) appeared to be consistent with the mapping of BRAF proteoform 1 peptides (Figure 3D).…”

Section: Resultsmentioning

confidence: 99%

Proteoform-level deconvolution reveals a broader spectrum of ibrutinib off-targets

Leo,

Kunold,

Anastasia

et al. 2023

Preprint

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Over the last decade, proteome-wide mapping of drug interactions has revealed that most targeted drugs bind to not only their intended targets, but additional proteins as well. However, the majority of these studies have focused on analyzing proteins as encoded by their genes, thus neglecting the fact that most proteins exist as dynamic populations of multiple proteoforms. Here, we addressed this problem by combining the use of thermal proteome profiling (TPP), a powerful method for proteome analysis, with proteoform detection to refine the target landscape of an approved drug, ibrutinib. We revealed that, in addition to known targets, ibrutinib exhibits an intricate network of interactions involving multiple different proteoforms. Notably, we discovered affinity for specific proteoforms that link ibrutinib to mechanisms in immunomodulation and cellular processes like Golgi trafficking, endosomal trafficking, and glycosylation. These insights provide a framework for interpreting clinically observed off-target and adverse events. More generally, our findings highlight the importance of proteoform-level deconvolution in understanding drug interactions and their functional impacts, and offer a critical perspective for drug mechanism studies and potential applications in precision medicine.

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Ibrutinib Blocks YAP1 Activation and Reverses BRAF Inhibitor Resistance in Melanoma Cells

Cited by 8 publications

References 69 publications

Epstein–Barr virus LMP1 protein promotes proliferation and inhibits differentiation of epithelial cells via activation of YAP and TAZ

Epstein–Barr virus LMP1 protein promotes proliferation and inhibits differentiation of epithelial cells via activation of YAP and TAZ

Reversal of cancer gene expression identifies repurposed drugs for diffuse intrinsic pontine glioma

Proteoform-level deconvolution reveals a broader spectrum of ibrutinib off-targets

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