Sorafenib suppresses JNK-dependent apoptosis through inhibition of ZAK

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

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

Sorafenib suppresses JNK-dependent apoptosis through inhibition of ZAK

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

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25 Scopus citations

Abstract

Sorafenib is U.S. Food and Drug Adminstration-approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers. Unfortunately, as with other RAF inhibitors, patients treated with sorafenib have a 5% to 10% rate of developing cutaneous squamous cell carcinoma (cSCC)/keratoacanthomas. Paradoxical activation of extracellular signal-regulated kinase (ERK) in BRAF wild-type cells has been implicated in RAF inhibitor-induced cSCC. Here, we report that sorafenib suppresses UV-induced apoptosis specifically by inhibiting c-jun-NH₂-kinase (JNK) activation through the off-target inhibition of leucine zipper and sterile alpha motif-containing kinase (ZAK). Our results implicate suppression of JNK signaling, independent of the ERK pathway, as an additional mechanism of adverse effects of sorafenib. This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis.

Original language	English (US)
Pages (from-to)	221-229
Number of pages	9
Journal	Molecular cancer therapeutics
Volume	13
Issue number	1
DOIs	https://doi.org/10.1158/1535-7163.MCT-13-0561
State	Published - Jan 2013

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1158/1535-7163.MCT-13-0561

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Vin, H., Ching, G., Ojeda, S. S., Adelmann, C. H., Chitsazzadeh, V., Dwyer, D. W., Ma, H., Ehrenreiter, K., Baccarini, M., Ruggieri, R., Curry, J. L., Ciurea, A. M., Duvic, M., Busaidy, N. L., Tannir, N. M., & Tsai, K. Y. (2013). Sorafenib suppresses JNK-dependent apoptosis through inhibition of ZAK. Molecular cancer therapeutics, 13(1), 221-229. https://doi.org/10.1158/1535-7163.MCT-13-0561

Vin, H, Ching, G, Ojeda, SS, Adelmann, CH, Chitsazzadeh, V, Dwyer, DW, Ma, H, Ehrenreiter, K, Baccarini, M, Ruggieri, R, Curry, JL , Ciurea, AM, Duvic, M, Busaidy, NL , Tannir, NM & Tsai, KY 2013, 'Sorafenib suppresses JNK-dependent apoptosis through inhibition of ZAK', Molecular cancer therapeutics, vol. 13, no. 1, pp. 221-229. https://doi.org/10.1158/1535-7163.MCT-13-0561

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abstract = "Sorafenib is U.S. Food and Drug Adminstration-approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers. Unfortunately, as with other RAF inhibitors, patients treated with sorafenib have a 5% to 10% rate of developing cutaneous squamous cell carcinoma (cSCC)/keratoacanthomas. Paradoxical activation of extracellular signal-regulated kinase (ERK) in BRAF wild-type cells has been implicated in RAF inhibitor-induced cSCC. Here, we report that sorafenib suppresses UV-induced apoptosis specifically by inhibiting c-jun-NH2-kinase (JNK) activation through the off-target inhibition of leucine zipper and sterile alpha motif-containing kinase (ZAK). Our results implicate suppression of JNK signaling, independent of the ERK pathway, as an additional mechanism of adverse effects of sorafenib. This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis.",

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

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AU - Dwyer, David W.

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AU - Ehrenreiter, Karin

AU - Baccarini, Manuela

AU - Ruggieri, Rosamaria

AU - Curry, Jonathan L.

AU - Ciurea, Ana M.

AU - Duvic, Madeleine

AU - Busaidy, Naifa L.

AU - Tannir, Nizar M.

AU - Tsai, Kenneth Y.

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AB - Sorafenib is U.S. Food and Drug Adminstration-approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers. Unfortunately, as with other RAF inhibitors, patients treated with sorafenib have a 5% to 10% rate of developing cutaneous squamous cell carcinoma (cSCC)/keratoacanthomas. Paradoxical activation of extracellular signal-regulated kinase (ERK) in BRAF wild-type cells has been implicated in RAF inhibitor-induced cSCC. Here, we report that sorafenib suppresses UV-induced apoptosis specifically by inhibiting c-jun-NH2-kinase (JNK) activation through the off-target inhibition of leucine zipper and sterile alpha motif-containing kinase (ZAK). Our results implicate suppression of JNK signaling, independent of the ERK pathway, as an additional mechanism of adverse effects of sorafenib. This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis.

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Sorafenib suppresses JNK-dependent apoptosis through inhibition of ZAK

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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