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PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors
Pancreatic neuroendocrine tumors (PNET) remain an unmet clinical need. In this study, we show that targeting both nicotinamide phosphoribosyltransferase (NAMPT) and p21-activated kinase 4 (PAK4) could become a synthetic lethal strategy for PNET. The expression of PAK4 and NAMPT was found to be highe...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966587/ https://www.ncbi.nlm.nih.gov/pubmed/31795447 http://dx.doi.org/10.3390/cancers11121902 |
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author | Mpilla, Gabriel Aboukameel, Amro Muqbil, Irfana Kim, Steve Beydoun, Rafic Philip, Philip A. Mohammad, Ramzi M. Kamgar, Mandana Shidham, Vinod Senapedis, William Baloglu, Erkan Li, Jing Dyson, Gregory Xue, Yue El-Rayes, Bassel Azmi, Asfar S. |
author_facet | Mpilla, Gabriel Aboukameel, Amro Muqbil, Irfana Kim, Steve Beydoun, Rafic Philip, Philip A. Mohammad, Ramzi M. Kamgar, Mandana Shidham, Vinod Senapedis, William Baloglu, Erkan Li, Jing Dyson, Gregory Xue, Yue El-Rayes, Bassel Azmi, Asfar S. |
author_sort | Mpilla, Gabriel |
collection | PubMed |
description | Pancreatic neuroendocrine tumors (PNET) remain an unmet clinical need. In this study, we show that targeting both nicotinamide phosphoribosyltransferase (NAMPT) and p21-activated kinase 4 (PAK4) could become a synthetic lethal strategy for PNET. The expression of PAK4 and NAMPT was found to be higher in PNET tissue compared to normal cells. PAK4-NAMPT dual RNAi suppressed proliferation of PNET cell lines. Treatment with KPT-9274 (currently in a Phase I trial or analogs, PF3758309 (the PAK4 selective inhibitor) or FK866 (the NAMPT inhibitor)) suppressed the growth of PNET cell lines and synergized with the mammalian target of rapamycin (mTOR) inhibitors everolimus and INK-128. Molecular analysis of the combination treatment showed down-regulation of known everolimus resistance drivers. KPT-9274 suppressed NAD pool and ATP levels in PNET cell lines. Metabolomic profiling showed a statistically significant alteration in cellular energetic pathways. KPT-9274 given orally at 150 mg/kg 5 days/week for 4 weeks dramatically reduced PNET sub-cutaneous tumor growth. Residual tumor analysis demonstrated target engagement in vivo and recapitulated in vitro results. Our investigations demonstrate that PAK4 and NAMPT are two viable therapeutic targets in the difficult to treat PNET that warrant further clinical investigation. |
format | Online Article Text |
id | pubmed-6966587 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69665872020-02-04 PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors Mpilla, Gabriel Aboukameel, Amro Muqbil, Irfana Kim, Steve Beydoun, Rafic Philip, Philip A. Mohammad, Ramzi M. Kamgar, Mandana Shidham, Vinod Senapedis, William Baloglu, Erkan Li, Jing Dyson, Gregory Xue, Yue El-Rayes, Bassel Azmi, Asfar S. Cancers (Basel) Article Pancreatic neuroendocrine tumors (PNET) remain an unmet clinical need. In this study, we show that targeting both nicotinamide phosphoribosyltransferase (NAMPT) and p21-activated kinase 4 (PAK4) could become a synthetic lethal strategy for PNET. The expression of PAK4 and NAMPT was found to be higher in PNET tissue compared to normal cells. PAK4-NAMPT dual RNAi suppressed proliferation of PNET cell lines. Treatment with KPT-9274 (currently in a Phase I trial or analogs, PF3758309 (the PAK4 selective inhibitor) or FK866 (the NAMPT inhibitor)) suppressed the growth of PNET cell lines and synergized with the mammalian target of rapamycin (mTOR) inhibitors everolimus and INK-128. Molecular analysis of the combination treatment showed down-regulation of known everolimus resistance drivers. KPT-9274 suppressed NAD pool and ATP levels in PNET cell lines. Metabolomic profiling showed a statistically significant alteration in cellular energetic pathways. KPT-9274 given orally at 150 mg/kg 5 days/week for 4 weeks dramatically reduced PNET sub-cutaneous tumor growth. Residual tumor analysis demonstrated target engagement in vivo and recapitulated in vitro results. Our investigations demonstrate that PAK4 and NAMPT are two viable therapeutic targets in the difficult to treat PNET that warrant further clinical investigation. MDPI 2019-11-29 /pmc/articles/PMC6966587/ /pubmed/31795447 http://dx.doi.org/10.3390/cancers11121902 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Mpilla, Gabriel Aboukameel, Amro Muqbil, Irfana Kim, Steve Beydoun, Rafic Philip, Philip A. Mohammad, Ramzi M. Kamgar, Mandana Shidham, Vinod Senapedis, William Baloglu, Erkan Li, Jing Dyson, Gregory Xue, Yue El-Rayes, Bassel Azmi, Asfar S. PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors |
title | PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors |
title_full | PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors |
title_fullStr | PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors |
title_full_unstemmed | PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors |
title_short | PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors |
title_sort | pak4-nampt dual inhibition as a novel strategy for therapy resistant pancreatic neuroendocrine tumors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966587/ https://www.ncbi.nlm.nih.gov/pubmed/31795447 http://dx.doi.org/10.3390/cancers11121902 |
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