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Rationally Repurposing Ruxolitinib (Jakafi(®)) as a Solid Tumor Therapeutic

We determined whether the approved myelofibrosis drug ruxolitinib (Jakafi(®)), an inhibitor of Janus kinases 1/2 (JAK1 and JAK2), could be repurposed as an anti-cancer agent for solid tumors. Ruxolitinib synergistically interacted with dual ERBB1/2/4 inhibitors to kill breast as well as lung, ovaria...

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Autores principales: Tavallai, Mehrad, Booth, Laurence, Roberts, Jane L., Poklepovic, Andrew, Dent, Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904019/
https://www.ncbi.nlm.nih.gov/pubmed/27379204
http://dx.doi.org/10.3389/fonc.2016.00142
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author Tavallai, Mehrad
Booth, Laurence
Roberts, Jane L.
Poklepovic, Andrew
Dent, Paul
author_facet Tavallai, Mehrad
Booth, Laurence
Roberts, Jane L.
Poklepovic, Andrew
Dent, Paul
author_sort Tavallai, Mehrad
collection PubMed
description We determined whether the approved myelofibrosis drug ruxolitinib (Jakafi(®)), an inhibitor of Janus kinases 1/2 (JAK1 and JAK2), could be repurposed as an anti-cancer agent for solid tumors. Ruxolitinib synergistically interacted with dual ERBB1/2/4 inhibitors to kill breast as well as lung, ovarian and brain cancer cells. Knock down of JAK1/2 or of ERBB1/2/3/4 recapitulated on-target drug effects. The combination of (ruxolitinib + ERBB1/2/4 inhibitor) rapidly inactivated AKT, mTORC1, mTORC2, STAT3, and STAT5, and activated eIF2α. In parallel, the drug combination reduced expression of MCL-1, BCL-XL, HSP90, HSP70, and GRP78, and increased expression of Beclin1. Activated forms of STAT3, AKT, or mTOR prevented the drug-induced decline in BCL-XL, MCL-1, HSP90, and HSP70 levels. Over-expression of chaperones maintained AKT/mTOR activity in the presence of drugs and protected tumor cells from the drug combination. Expression of dominant negative eIF2α S51A prevented the increase in Beclin1 expression and protected tumor cells from the drug combination. Loss of mTOR activity was associated with increased ATG13 S318 phosphorylation and with autophagosome formation. Autophagosomes initially co-localized with mitochondria and subsequently with lysosomes. Knock down of Beclin1 suppressed: drug-induced mitophagy; the activation of the toxic BH3 domain proteins BAX and BAK; and tumor cell killing. Knock down of apoptosis-inducing factor (AIF) protected tumor cells from the drug combination, whereas blockade of caspase 9 signaling did not. The drug combination released AIF into the cytosol and increased nuclear AIF: eIF3A co-localization. A 4-day transient exposure of orthotopic tumors to (ruxolitinib + afatinib) profoundly reduced mammary tumor growth over the following 35 days. Re-grown tumors exhibited high levels of BAD S112 phosphorylation and activation of ERK1/2 and NFκB. Our data demonstrate that mitophagy is an essential component of (ruxolitinib + ERBB inhibitor) lethality and that this drug combination should be explored in a phase I trial in solid tumor patients.
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spelling pubmed-49040192016-07-04 Rationally Repurposing Ruxolitinib (Jakafi(®)) as a Solid Tumor Therapeutic Tavallai, Mehrad Booth, Laurence Roberts, Jane L. Poklepovic, Andrew Dent, Paul Front Oncol Oncology We determined whether the approved myelofibrosis drug ruxolitinib (Jakafi(®)), an inhibitor of Janus kinases 1/2 (JAK1 and JAK2), could be repurposed as an anti-cancer agent for solid tumors. Ruxolitinib synergistically interacted with dual ERBB1/2/4 inhibitors to kill breast as well as lung, ovarian and brain cancer cells. Knock down of JAK1/2 or of ERBB1/2/3/4 recapitulated on-target drug effects. The combination of (ruxolitinib + ERBB1/2/4 inhibitor) rapidly inactivated AKT, mTORC1, mTORC2, STAT3, and STAT5, and activated eIF2α. In parallel, the drug combination reduced expression of MCL-1, BCL-XL, HSP90, HSP70, and GRP78, and increased expression of Beclin1. Activated forms of STAT3, AKT, or mTOR prevented the drug-induced decline in BCL-XL, MCL-1, HSP90, and HSP70 levels. Over-expression of chaperones maintained AKT/mTOR activity in the presence of drugs and protected tumor cells from the drug combination. Expression of dominant negative eIF2α S51A prevented the increase in Beclin1 expression and protected tumor cells from the drug combination. Loss of mTOR activity was associated with increased ATG13 S318 phosphorylation and with autophagosome formation. Autophagosomes initially co-localized with mitochondria and subsequently with lysosomes. Knock down of Beclin1 suppressed: drug-induced mitophagy; the activation of the toxic BH3 domain proteins BAX and BAK; and tumor cell killing. Knock down of apoptosis-inducing factor (AIF) protected tumor cells from the drug combination, whereas blockade of caspase 9 signaling did not. The drug combination released AIF into the cytosol and increased nuclear AIF: eIF3A co-localization. A 4-day transient exposure of orthotopic tumors to (ruxolitinib + afatinib) profoundly reduced mammary tumor growth over the following 35 days. Re-grown tumors exhibited high levels of BAD S112 phosphorylation and activation of ERK1/2 and NFκB. Our data demonstrate that mitophagy is an essential component of (ruxolitinib + ERBB inhibitor) lethality and that this drug combination should be explored in a phase I trial in solid tumor patients. Frontiers Media S.A. 2016-06-13 /pmc/articles/PMC4904019/ /pubmed/27379204 http://dx.doi.org/10.3389/fonc.2016.00142 Text en Copyright © 2016 Tavallai, Booth, Roberts, Poklepovic and Dent. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Tavallai, Mehrad
Booth, Laurence
Roberts, Jane L.
Poklepovic, Andrew
Dent, Paul
Rationally Repurposing Ruxolitinib (Jakafi(®)) as a Solid Tumor Therapeutic
title Rationally Repurposing Ruxolitinib (Jakafi(®)) as a Solid Tumor Therapeutic
title_full Rationally Repurposing Ruxolitinib (Jakafi(®)) as a Solid Tumor Therapeutic
title_fullStr Rationally Repurposing Ruxolitinib (Jakafi(®)) as a Solid Tumor Therapeutic
title_full_unstemmed Rationally Repurposing Ruxolitinib (Jakafi(®)) as a Solid Tumor Therapeutic
title_short Rationally Repurposing Ruxolitinib (Jakafi(®)) as a Solid Tumor Therapeutic
title_sort rationally repurposing ruxolitinib (jakafi(®)) as a solid tumor therapeutic
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904019/
https://www.ncbi.nlm.nih.gov/pubmed/27379204
http://dx.doi.org/10.3389/fonc.2016.00142
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