Sorafenib Suppresses JNK-Dependent Apoptosis through Inhibition of ZAK

Vin, Harina; Ching, Grace; Ojeda, Sandra S.; Adelmann, Charles H.; Chitsazzadeh, Vida; Dwyer, David; Ma, Haiching; Ehrenreiter, Karin; Baccarini, Manuela; Ruggieri, Rosamaria; Curry, Jonathan L.; Ciurea, Ana M.; Duvic, Madeleine; Busaidy, Naifa L.; Tannir, Nizar M.; Tsai, Kenneth Y.

doi:10.1158/1535-7163.mct-13-0561

Cited by 27 publications

(28 citation statements)

References 40 publications

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“…Sorafenib, a multi kinase inhibitor (including C-Raf, B-Raf and VEGF) approved for the treatment of kidney and liver cancers also inhibits ZAK at an IC50 of 48.6 nM [27]. Adverse events of Sorafenib in patients undergoing chemotherapy have been ascribed to the ZAK targeted activity of the agent.…”

Section: Discussionmentioning

confidence: 99%

A Requirement for ZAK Kinase Activity in Canonical TGF-β Signaling

Nyati

Chator

Schinske

et al. 2016

Translational Oncology

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The sterile alpha motif and leucine zipper containing kinase ZAK (AZK, MLT, MLK7), is a MAPK-kinase kinase (MKKK). Like most MAPKKKs which are known to activate the c-Jun. amino-terminal kinase (JNK) pathway, ZAK has been shown to participate in the transduction of Transforming growth factor-β (TGF-β)-mediated non-canonical signaling. A role for ZAK in SMAD-dependent, canonical TGF-β signaling has not been previously appreciated. Using a combination of functional genomics and biochemical techniques, we demonstrate that ZAK regulates canonical TGFβRI/II signaling in lung and breast cancer cell lines and may serve as a key node in the regulation of TGFBR kinase activity. Remarkably, we demonstrate that siRNA mediated depletion of ZAK strongly inhibited TGF-β dependent SMAD2/3 activation and subsequent promoter activation (SMAD binding element driven luciferase expression; SBE4-Luc). A ZAK specific inhibitor (DHP-2), dose-dependently activated the bioluminescent TGFBR-kinase activity reporter (BTR), blocked TGF-β induced SMAD2/3 phosphorylation and SBE4-Luc activation and cancer cell-invasion. In aggregate, these findings identify a novel role for the ZAK kinase in canonical TGF-β signaling and an invasive cancer cell phenotype thus providing a novel target for TGF-β inhibition.

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Section: Discussionmentioning

confidence: 99%

A Requirement for ZAK Kinase Activity in Canonical TGF-β Signaling

Nyati

Chator

Schinske

et al. 2016

Translational Oncology

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“…However, small molecule inhibitor therapy aimed at specific protein targets within the MAPK/ERK pathway has resulted in the development of secondary malignancies. RAF inhibitors, as a class, may cause abnormal skin cell proliferation, leading to keratoacanthomas or squamous cell cancers in approximately 10% to 20% of patients . The development of these lesions is caused by paradoxical activation of the normal MAPK/ERK pathway in the genomically normal skin keratinocytes .…”

Section: Introductionmentioning

confidence: 99%

The MAPK pathway across different malignancies: A new perspective

Burotto

Chiou

Lee

et al. 2014

Cancer

755

557

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The MAPK/ERK pathway is activated by upstream genomic events and/or activation of multiple signaling events where information coalesces at this important nodal pathway point. This pathway is tightly regulated under normal conditions by phosphatases and bidirectional communication with other pathways, such as the AKT/m-TOR pathway. Recent evidence indicates that the MAPK/ERK signaling node can function as a tumor suppressor as well as the more common pro-oncogenic signal. The effect that predominates depends on the intensity of the signal and the context or tissue in which the signal is aberrantly activated. Genomic profiling of tumors has revealed common mutations in MAPK/ERK pathway components, such as BRAF. Currently approved for the treatment of melanoma, inhibitors of B-RAF kinase (BRAFi) are being studied alone and in combination with inhibitors of the MAPK and other pathways to optimize treatment of many tumor types. Therapies targeted toward MAPK/ERK components have variable response rates when used in different solid tumors, such as colorectal cancer and ovarian cancer. Understanding the differential nature of activation of the MAPK/ERK pathway in each tumor type is critical in developing single and combination regimens, as different tumors have unique mechanisms of primary and secondary signaling and subsequent sensitivity to drugs.

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“…Since many of the cSCC occur on sun-exposed skin areas, UV light has been assumed to be the trigger of cSCC development. (20) Both the knockdown of ZAK and the administration of compounds with ZAK inhibitory activity prevented UV light from inducing apoptosis in cancer cells. (20),(21) Moreover, ZAK inhibition accelerated the UV light-driven development of cSCC in the hairless mouse model.…”

Section: Introductionmentioning

confidence: 99%

“…(20) Both the knockdown of ZAK and the administration of compounds with ZAK inhibitory activity prevented UV light from inducing apoptosis in cancer cells. (20),(21) Moreover, ZAK inhibition accelerated the UV light-driven development of cSCC in the hairless mouse model. (20),(21) A prominent alternative model to explain cSCC formation is the inhibitor-driven paradoxical B-RAF activation.…”

Section: Introductionmentioning

confidence: 99%

“…(20),(21) Moreover, ZAK inhibition accelerated the UV light-driven development of cSCC in the hairless mouse model. (20),(21) A prominent alternative model to explain cSCC formation is the inhibitor-driven paradoxical B-RAF activation. (25) Which model may be more valid under physiological conditions or whether both mechanisms cooperate to promote cSCC formation is still under debate.…”

Section: Introductionmentioning

confidence: 99%

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Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib

et al. 2016

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The mixed lineage kinase ZAK is a key regulator of the MAPK pathway mediating cell survival and inflammatory response. ZAK is targeted by several clinically approved kinase inhibitors, and inhibition of ZAK has been reported to protect from doxorubicin-induced cardiomyopathy. On the other hand, unintended targeting of ZAK has been linked to severe adverse effects such as the development of cutaneous squamous cell carcinoma. Therefore, both specific inhibitors of ZAK, as well as anticancer drugs lacking off-target activity against ZAK, may provide therapeutic benefit. Here we report the first crystal structure of ZAK in complex with the B-RAF inhibitor vemurafenib. The co-crystal structure displayed a number of ZAK-specific features including a highly distorted P loop conformation enabling rational inhibitor design. Positional scanning peptide library analysis revealed a unique substrate specificity of the ZAK kinase including unprecedented preferences for histidine residues at positions −1 and +2 relative to the phosphoacceptor site. In addition, we screened a library of clinical kinase inhibitors identifying several inhibitors that potently inhibit ZAK, demonstrating that this kinase is commonly mistargeted by currently used anticancer drugs.

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Sorafenib Suppresses JNK-Dependent Apoptosis through Inhibition of ZAK

Cited by 27 publications

References 40 publications

A Requirement for ZAK Kinase Activity in Canonical TGF-β Signaling

A Requirement for ZAK Kinase Activity in Canonical TGF-β Signaling

The MAPK pathway across different malignancies: A new perspective

Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib

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