Cargando…

AXL Inhibition Enhances MEK Inhibitor Sensitivity in Malignant Peripheral Nerve Sheath Tumors

Dysregulation of the receptor tyrosine kinase AXL is known to promote cancer cell growth and survival in many sarcomas, including the rare subtype, malignant peripheral nerve sheath tumors (MPNST). MPNSTs are largely chemoresistant and carry a poor prognosis. AXL is an attractive potential therapeut...

Descripción completa

Detalles Bibliográficos
Autores principales: Landers, Sharon M., Bhalla, Angela D., Ma, XiaoYan, Lusby, Kristelle, Ingram, Davis, Al Sannaa, Ghadah, Wang, Wei-Lien, Lazar, Alexander J., Torres, Keila E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717506/
https://www.ncbi.nlm.nih.gov/pubmed/33283192
http://dx.doi.org/10.26502/jcsct.5079091
_version_ 1783619322532331520
author Landers, Sharon M.
Bhalla, Angela D.
Ma, XiaoYan
Lusby, Kristelle
Ingram, Davis
Al Sannaa, Ghadah
Wang, Wei-Lien
Lazar, Alexander J.
Torres, Keila E.
author_facet Landers, Sharon M.
Bhalla, Angela D.
Ma, XiaoYan
Lusby, Kristelle
Ingram, Davis
Al Sannaa, Ghadah
Wang, Wei-Lien
Lazar, Alexander J.
Torres, Keila E.
author_sort Landers, Sharon M.
collection PubMed
description Dysregulation of the receptor tyrosine kinase AXL is known to promote cancer cell growth and survival in many sarcomas, including the rare subtype, malignant peripheral nerve sheath tumors (MPNST). MPNSTs are largely chemoresistant and carry a poor prognosis. AXL is an attractive potential therapeutic target, as it is aberrantly expressed, and its activation may be an early event in MPNST. However, the effect of AXL inhibition on MPNST development and progression is not known. Here, we investigated the role of AXL in MPNST development and the effects of AXL and MEK1/2 co-inhibition on MPNSTs. We used western blotting to examine AXL expression and activation in MPNST cell lines. We analyzed the effects of exogenous growth arrest-specific 6 (GAS6) expression on downstream signaling and the proliferation, migration, and invasion of MPNST cells. The effect of AXL knockdown with or without mitogen-activated protein kinase (MAPK) inhibition on downstream signal transduction and tumorigenesis was also examined in vivo and in vitro. We found that AXL knockdown increased MAPK pathway signaling. This compensation, in turn, abrogated the antitumorigenic effects linked to AXL knockdown in vivo. AXL knockdown, combined with pharmacological MEK inhibition, reduced the proliferation and increased the apoptosis of MPNST cells both in vitro and in vivo. The pharmacological co-inhibition of AXL and MEK1/2 reduced MPNST volumes. Together these findings suggest that AXL inhibition enhances the sensitivity of MPNST to other small molecule inhibitors. We conclude that combination therapy with AXL inhibitor may be a therapeutic option for MPNST.
format Online
Article
Text
id pubmed-7717506
institution National Center for Biotechnology Information
language English
publishDate 2020
record_format MEDLINE/PubMed
spelling pubmed-77175062020-12-04 AXL Inhibition Enhances MEK Inhibitor Sensitivity in Malignant Peripheral Nerve Sheath Tumors Landers, Sharon M. Bhalla, Angela D. Ma, XiaoYan Lusby, Kristelle Ingram, Davis Al Sannaa, Ghadah Wang, Wei-Lien Lazar, Alexander J. Torres, Keila E. J Cancer Sci Clin Ther Article Dysregulation of the receptor tyrosine kinase AXL is known to promote cancer cell growth and survival in many sarcomas, including the rare subtype, malignant peripheral nerve sheath tumors (MPNST). MPNSTs are largely chemoresistant and carry a poor prognosis. AXL is an attractive potential therapeutic target, as it is aberrantly expressed, and its activation may be an early event in MPNST. However, the effect of AXL inhibition on MPNST development and progression is not known. Here, we investigated the role of AXL in MPNST development and the effects of AXL and MEK1/2 co-inhibition on MPNSTs. We used western blotting to examine AXL expression and activation in MPNST cell lines. We analyzed the effects of exogenous growth arrest-specific 6 (GAS6) expression on downstream signaling and the proliferation, migration, and invasion of MPNST cells. The effect of AXL knockdown with or without mitogen-activated protein kinase (MAPK) inhibition on downstream signal transduction and tumorigenesis was also examined in vivo and in vitro. We found that AXL knockdown increased MAPK pathway signaling. This compensation, in turn, abrogated the antitumorigenic effects linked to AXL knockdown in vivo. AXL knockdown, combined with pharmacological MEK inhibition, reduced the proliferation and increased the apoptosis of MPNST cells both in vitro and in vivo. The pharmacological co-inhibition of AXL and MEK1/2 reduced MPNST volumes. Together these findings suggest that AXL inhibition enhances the sensitivity of MPNST to other small molecule inhibitors. We conclude that combination therapy with AXL inhibitor may be a therapeutic option for MPNST. 2020-10-27 2020 /pmc/articles/PMC7717506/ /pubmed/33283192 http://dx.doi.org/10.26502/jcsct.5079091 Text en This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license 4.0 (http://creativecommons.org/licenses/by/4.0/)
spellingShingle Article
Landers, Sharon M.
Bhalla, Angela D.
Ma, XiaoYan
Lusby, Kristelle
Ingram, Davis
Al Sannaa, Ghadah
Wang, Wei-Lien
Lazar, Alexander J.
Torres, Keila E.
AXL Inhibition Enhances MEK Inhibitor Sensitivity in Malignant Peripheral Nerve Sheath Tumors
title AXL Inhibition Enhances MEK Inhibitor Sensitivity in Malignant Peripheral Nerve Sheath Tumors
title_full AXL Inhibition Enhances MEK Inhibitor Sensitivity in Malignant Peripheral Nerve Sheath Tumors
title_fullStr AXL Inhibition Enhances MEK Inhibitor Sensitivity in Malignant Peripheral Nerve Sheath Tumors
title_full_unstemmed AXL Inhibition Enhances MEK Inhibitor Sensitivity in Malignant Peripheral Nerve Sheath Tumors
title_short AXL Inhibition Enhances MEK Inhibitor Sensitivity in Malignant Peripheral Nerve Sheath Tumors
title_sort axl inhibition enhances mek inhibitor sensitivity in malignant peripheral nerve sheath tumors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717506/
https://www.ncbi.nlm.nih.gov/pubmed/33283192
http://dx.doi.org/10.26502/jcsct.5079091
work_keys_str_mv AT landerssharonm axlinhibitionenhancesmekinhibitorsensitivityinmalignantperipheralnervesheathtumors
AT bhallaangelad axlinhibitionenhancesmekinhibitorsensitivityinmalignantperipheralnervesheathtumors
AT maxiaoyan axlinhibitionenhancesmekinhibitorsensitivityinmalignantperipheralnervesheathtumors
AT lusbykristelle axlinhibitionenhancesmekinhibitorsensitivityinmalignantperipheralnervesheathtumors
AT ingramdavis axlinhibitionenhancesmekinhibitorsensitivityinmalignantperipheralnervesheathtumors
AT alsannaaghadah axlinhibitionenhancesmekinhibitorsensitivityinmalignantperipheralnervesheathtumors
AT wangweilien axlinhibitionenhancesmekinhibitorsensitivityinmalignantperipheralnervesheathtumors
AT lazaralexanderj axlinhibitionenhancesmekinhibitorsensitivityinmalignantperipheralnervesheathtumors
AT torreskeilae axlinhibitionenhancesmekinhibitorsensitivityinmalignantperipheralnervesheathtumors