PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma

Abstract Despite increasing incidence, treatment for hepatoblastoma has not changed significantly over the past 20 years. Chemotherapeutic strategies continue to rely on cisplatin, as it remains the most active single agent against hepatoblastoma. However, chemoresistance remains a significant chall...

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Autores principales:	Raoud Marayati, Laura L. Stafman, Adele P. Williams, Laura V. Bownes, Colin H. Quinn, Jamie M. Aye, Jerry E. Stewart, Karina J. Yoon, Joshua C. Anderson, Christopher D. Willey, Elizabeth A. Beierle
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/651d99d3286c48f987b6b07498bbc8c8
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spelling	oai:doaj.org-article:651d99d3286c48f987b6b07498bbc8c82021-12-02T16:30:46ZPIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma10.1038/s41598-021-85289-02045-2322https://doaj.org/article/651d99d3286c48f987b6b07498bbc8c82021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85289-0https://doaj.org/toc/2045-2322Abstract Despite increasing incidence, treatment for hepatoblastoma has not changed significantly over the past 20 years. Chemotherapeutic strategies continue to rely on cisplatin, as it remains the most active single agent against hepatoblastoma. However, chemoresistance remains a significant challenge with 54–80% of patients developing resistance to chemotherapy after 4–5 cycles of treatment. Stem cell-like cancer cells (SCLCCs) are a subset of cells thought to play a role in chemoresistance and disease recurrence. We have previously demonstrated that Proviral Integration site for Moloney murine leukemia virus (PIM) kinases, specifically PIM3, play a role in hepatoblastoma cell proliferation and tumor growth and maintain the SCLCC phenotype. Here, we describe the development of a cisplatin-resistant hepatoblastoma xenograft model of the human HuH6 cell line and a patient-derived xenograft, COA67. We provide evidence that these cisplatin-resistant cells are enriched for SCLCCs and express PIM3 at higher levels than cisplatin-naïve cells. We demonstrate that PIM inhibition with AZD1208 sensitizes cisplatin-resistant hepatoblastoma cells to cisplatin, enhances cisplatin-mediated apoptosis, and decreases the SCLCC phenotype seen with cisplatin resistance. Together, these findings indicate that PIM inhibition may be a promising adjunct in the treatment of hepatoblastoma to effectively target SCLCCs and potentially decrease chemoresistance and subsequent disease relapse.Raoud MarayatiLaura L. StafmanAdele P. WilliamsLaura V. BownesColin H. QuinnJamie M. AyeJerry E. StewartKarina J. YoonJoshua C. AndersonChristopher D. WilleyElizabeth A. BeierleNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Raoud Marayati Laura L. Stafman Adele P. Williams Laura V. Bownes Colin H. Quinn Jamie M. Aye Jerry E. Stewart Karina J. Yoon Joshua C. Anderson Christopher D. Willey Elizabeth A. Beierle PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma
description	Abstract Despite increasing incidence, treatment for hepatoblastoma has not changed significantly over the past 20 years. Chemotherapeutic strategies continue to rely on cisplatin, as it remains the most active single agent against hepatoblastoma. However, chemoresistance remains a significant challenge with 54–80% of patients developing resistance to chemotherapy after 4–5 cycles of treatment. Stem cell-like cancer cells (SCLCCs) are a subset of cells thought to play a role in chemoresistance and disease recurrence. We have previously demonstrated that Proviral Integration site for Moloney murine leukemia virus (PIM) kinases, specifically PIM3, play a role in hepatoblastoma cell proliferation and tumor growth and maintain the SCLCC phenotype. Here, we describe the development of a cisplatin-resistant hepatoblastoma xenograft model of the human HuH6 cell line and a patient-derived xenograft, COA67. We provide evidence that these cisplatin-resistant cells are enriched for SCLCCs and express PIM3 at higher levels than cisplatin-naïve cells. We demonstrate that PIM inhibition with AZD1208 sensitizes cisplatin-resistant hepatoblastoma cells to cisplatin, enhances cisplatin-mediated apoptosis, and decreases the SCLCC phenotype seen with cisplatin resistance. Together, these findings indicate that PIM inhibition may be a promising adjunct in the treatment of hepatoblastoma to effectively target SCLCCs and potentially decrease chemoresistance and subsequent disease relapse.
format	article
author	Raoud Marayati Laura L. Stafman Adele P. Williams Laura V. Bownes Colin H. Quinn Jamie M. Aye Jerry E. Stewart Karina J. Yoon Joshua C. Anderson Christopher D. Willey Elizabeth A. Beierle
author_facet	Raoud Marayati Laura L. Stafman Adele P. Williams Laura V. Bownes Colin H. Quinn Jamie M. Aye Jerry E. Stewart Karina J. Yoon Joshua C. Anderson Christopher D. Willey Elizabeth A. Beierle
author_sort	Raoud Marayati
title	PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma
title_short	PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma
title_full	PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma
title_fullStr	PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma
title_full_unstemmed	PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma
title_sort	pim kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/651d99d3286c48f987b6b07498bbc8c8
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PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma

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