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Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor

SIMPLE SUMMARY: Imatinib mesylate (IM, Gleevec) has remained first-line therapy for most gastrointestinal stromal tumor (GIST) patients since 2002. During this time, three additional inhibitors have been approved for treatment of IM-refractory tumors; however, disease stabilization for these agents...

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Autores principales: Kozinova, Marya, Joshi, Shalina, Ye, Shuai, Belinsky, Martin G., Sharipova, Dinara, Farma, Jeffrey M., Reddy, Sanjay S., Litwin, Samuel, Devarajan, Karthik, Campos, Alex Rosa, Yu, Yi, Schwartz, Brian, von Mehren, Margaret, Rink, Lori
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345102/
https://www.ncbi.nlm.nih.gov/pubmed/34359600
http://dx.doi.org/10.3390/cancers13153699
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author Kozinova, Marya
Joshi, Shalina
Ye, Shuai
Belinsky, Martin G.
Sharipova, Dinara
Farma, Jeffrey M.
Reddy, Sanjay S.
Litwin, Samuel
Devarajan, Karthik
Campos, Alex Rosa
Yu, Yi
Schwartz, Brian
von Mehren, Margaret
Rink, Lori
author_facet Kozinova, Marya
Joshi, Shalina
Ye, Shuai
Belinsky, Martin G.
Sharipova, Dinara
Farma, Jeffrey M.
Reddy, Sanjay S.
Litwin, Samuel
Devarajan, Karthik
Campos, Alex Rosa
Yu, Yi
Schwartz, Brian
von Mehren, Margaret
Rink, Lori
author_sort Kozinova, Marya
collection PubMed
description SIMPLE SUMMARY: Imatinib mesylate (IM, Gleevec) has remained first-line therapy for most gastrointestinal stromal tumor (GIST) patients since 2002. During this time, three additional inhibitors have been approved for treatment of IM-refractory tumors; however, disease stabilization for these agents is measured in months. Once all approved lines of therapy are ineffective, patients with advanced GIST are left without treatment options. Therefore, preventing or delaying development of acquired resistance to IM could have clinical benefits. Activation of the PI3K/AKT signaling pathway has been associated with resistance to IM in GIST. We evaluated MK-4440, a novel AKT inhibitor, in combination with IM in GIST cells and mouse models. Our studies demonstrate superior activity of MK-4440/IM combination in a panel of GIST cell lines caused by cell cycle arrest and elevated PDCD4 expression leading to increased cell death. Furthermore, dual inhibition of KIT and AKT provided impressive disease stabilization in IM-sensitive GIST growing in mice. ABSTRACT: The majority of gastrointestinal stromal tumor (GIST) patients develop resistance to the first-line KIT inhibitor, imatinib mesylate (IM), through acquisition of secondary mutations in KIT or bypass signaling pathway activation. In addition to KIT, AKT is a relevant target for inhibition, since the PI3K/AKT pathway is crucial for IM-resistant GIST survival. We evaluated the activity of a novel pan-AKT inhibitor, MK-4440 (formerly ARQ 751), as monotherapy and in combination with IM in GIST cell lines and preclinical models with varying IM sensitivities. Dual inhibition of KIT and AKT demonstrated synergistic effects in IM-sensitive and -resistant GIST cell lines. Proteomic analyses revealed upregulation of the tumor suppressor, PDCD4, in combination treated cells. Enhanced PDCD4 expression correlated to increased cell death. In vivo studies revealed superior efficacy of MK-4440/IM combination in an IM-sensitive preclinical model of GIST compared with either single agent. The combination demonstrated limited efficacy in two IM-resistant models, including a GIST patient-derived xenograft model possessing an exon 9 KIT mutation. These studies provide strong rationale for further use of AKT inhibition in combination with IM in primary GIST; however, alternative agents will need to be tested in combination with AKT inhibition in the resistant setting.
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spelling pubmed-83451022021-08-07 Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor Kozinova, Marya Joshi, Shalina Ye, Shuai Belinsky, Martin G. Sharipova, Dinara Farma, Jeffrey M. Reddy, Sanjay S. Litwin, Samuel Devarajan, Karthik Campos, Alex Rosa Yu, Yi Schwartz, Brian von Mehren, Margaret Rink, Lori Cancers (Basel) Article SIMPLE SUMMARY: Imatinib mesylate (IM, Gleevec) has remained first-line therapy for most gastrointestinal stromal tumor (GIST) patients since 2002. During this time, three additional inhibitors have been approved for treatment of IM-refractory tumors; however, disease stabilization for these agents is measured in months. Once all approved lines of therapy are ineffective, patients with advanced GIST are left without treatment options. Therefore, preventing or delaying development of acquired resistance to IM could have clinical benefits. Activation of the PI3K/AKT signaling pathway has been associated with resistance to IM in GIST. We evaluated MK-4440, a novel AKT inhibitor, in combination with IM in GIST cells and mouse models. Our studies demonstrate superior activity of MK-4440/IM combination in a panel of GIST cell lines caused by cell cycle arrest and elevated PDCD4 expression leading to increased cell death. Furthermore, dual inhibition of KIT and AKT provided impressive disease stabilization in IM-sensitive GIST growing in mice. ABSTRACT: The majority of gastrointestinal stromal tumor (GIST) patients develop resistance to the first-line KIT inhibitor, imatinib mesylate (IM), through acquisition of secondary mutations in KIT or bypass signaling pathway activation. In addition to KIT, AKT is a relevant target for inhibition, since the PI3K/AKT pathway is crucial for IM-resistant GIST survival. We evaluated the activity of a novel pan-AKT inhibitor, MK-4440 (formerly ARQ 751), as monotherapy and in combination with IM in GIST cell lines and preclinical models with varying IM sensitivities. Dual inhibition of KIT and AKT demonstrated synergistic effects in IM-sensitive and -resistant GIST cell lines. Proteomic analyses revealed upregulation of the tumor suppressor, PDCD4, in combination treated cells. Enhanced PDCD4 expression correlated to increased cell death. In vivo studies revealed superior efficacy of MK-4440/IM combination in an IM-sensitive preclinical model of GIST compared with either single agent. The combination demonstrated limited efficacy in two IM-resistant models, including a GIST patient-derived xenograft model possessing an exon 9 KIT mutation. These studies provide strong rationale for further use of AKT inhibition in combination with IM in primary GIST; however, alternative agents will need to be tested in combination with AKT inhibition in the resistant setting. MDPI 2021-07-23 /pmc/articles/PMC8345102/ /pubmed/34359600 http://dx.doi.org/10.3390/cancers13153699 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kozinova, Marya
Joshi, Shalina
Ye, Shuai
Belinsky, Martin G.
Sharipova, Dinara
Farma, Jeffrey M.
Reddy, Sanjay S.
Litwin, Samuel
Devarajan, Karthik
Campos, Alex Rosa
Yu, Yi
Schwartz, Brian
von Mehren, Margaret
Rink, Lori
Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor
title Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor
title_full Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor
title_fullStr Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor
title_full_unstemmed Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor
title_short Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor
title_sort combined inhibition of akt and kit restores expression of programmed cell death 4 (pdcd4) in gastrointestinal stromal tumor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345102/
https://www.ncbi.nlm.nih.gov/pubmed/34359600
http://dx.doi.org/10.3390/cancers13153699
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