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Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance
Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we...
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/PMC6982268/ https://www.ncbi.nlm.nih.gov/pubmed/31905765 http://dx.doi.org/10.3390/ijms21010237 |
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author | Khan, Husain Yar Ge, James Nagasaka, Misako Aboukameel, Amro Mpilla, Gabriel Muqbil, Irfana Szlaczky, Mark Chaker, Mahmoud Baloglu, Erkan Landesman, Yosef Mohammad, Ramzi M. Azmi, Asfar S. Sukari, Ammar |
author_facet | Khan, Husain Yar Ge, James Nagasaka, Misako Aboukameel, Amro Mpilla, Gabriel Muqbil, Irfana Szlaczky, Mark Chaker, Mahmoud Baloglu, Erkan Landesman, Yosef Mohammad, Ramzi M. Azmi, Asfar S. Sukari, Ammar |
author_sort | Khan, Husain Yar |
collection | PubMed |
description | Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we examined the molecular profile of anaplastic thyroid cancer cells (8505C) exposed to lenvatinib and found that long-term exposure to lenvatinib caused phenotypic changes. Consistent with change toward mesenchymal morphology, activation of pro-survival signaling, nuclear exporter protein exportin 1 (XPO1) and Rho GTPase effector p21 activated kinases (PAK) was also observed. RNA-seq analysis showed that prolonged lenvatinib treatment caused alterations in numerous cellular pathways and several oncogenes such as CEACAM (carcinoembryonic antigen-related cell adhesion molecule) and NUPR1 (Nuclear protein 1) were also upregulated. Further, we evaluated the impact of XPO1 and PAK4 inhibition in the presence or absence of lenvatinib. Targeted inhibition of XPO1 and PAK4 could sensitize the 8505C cells to lenvatinib. Both XPO1 and PAK4 inhibitors, when combined with lenvatinib, showed superior anti-tumor activity in 8505C sub-cutaneous xenograft. These studies bring forward novel drug combinations to complement lenvatinib for treating anaplastic thyroid cancer. Such combinations may possibly reduce the chances of lenvatinib resistance in thyroid cancer patients. |
format | Online Article Text |
id | pubmed-6982268 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69822682020-02-07 Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance Khan, Husain Yar Ge, James Nagasaka, Misako Aboukameel, Amro Mpilla, Gabriel Muqbil, Irfana Szlaczky, Mark Chaker, Mahmoud Baloglu, Erkan Landesman, Yosef Mohammad, Ramzi M. Azmi, Asfar S. Sukari, Ammar Int J Mol Sci Article Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we examined the molecular profile of anaplastic thyroid cancer cells (8505C) exposed to lenvatinib and found that long-term exposure to lenvatinib caused phenotypic changes. Consistent with change toward mesenchymal morphology, activation of pro-survival signaling, nuclear exporter protein exportin 1 (XPO1) and Rho GTPase effector p21 activated kinases (PAK) was also observed. RNA-seq analysis showed that prolonged lenvatinib treatment caused alterations in numerous cellular pathways and several oncogenes such as CEACAM (carcinoembryonic antigen-related cell adhesion molecule) and NUPR1 (Nuclear protein 1) were also upregulated. Further, we evaluated the impact of XPO1 and PAK4 inhibition in the presence or absence of lenvatinib. Targeted inhibition of XPO1 and PAK4 could sensitize the 8505C cells to lenvatinib. Both XPO1 and PAK4 inhibitors, when combined with lenvatinib, showed superior anti-tumor activity in 8505C sub-cutaneous xenograft. These studies bring forward novel drug combinations to complement lenvatinib for treating anaplastic thyroid cancer. Such combinations may possibly reduce the chances of lenvatinib resistance in thyroid cancer patients. MDPI 2019-12-29 /pmc/articles/PMC6982268/ /pubmed/31905765 http://dx.doi.org/10.3390/ijms21010237 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 Khan, Husain Yar Ge, James Nagasaka, Misako Aboukameel, Amro Mpilla, Gabriel Muqbil, Irfana Szlaczky, Mark Chaker, Mahmoud Baloglu, Erkan Landesman, Yosef Mohammad, Ramzi M. Azmi, Asfar S. Sukari, Ammar Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance |
title | Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance |
title_full | Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance |
title_fullStr | Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance |
title_full_unstemmed | Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance |
title_short | Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance |
title_sort | targeting xpo1 and pak4 in 8505c anaplastic thyroid cancer cells: putative implications for overcoming lenvatinib therapy resistance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982268/ https://www.ncbi.nlm.nih.gov/pubmed/31905765 http://dx.doi.org/10.3390/ijms21010237 |
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