Targeting mTOR with MLN0128 Overcomes Rapamycin and Chemoresistant Primary Effusion Lymphoma

ABSTRACT Primary effusion lymphoma (PEL) is caused by Kaposi’s sarcoma-associated herpesvirus (KSHV). PEL has a highly active mTOR pathway, which makes mTOR a potential therapeutic target. MLN0128 is an ATP-competitive inhibitor of mTOR that has entered clinical trials for solid tumors. Our results...

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Autores principales:	Carolina Caro-Vegas, Aubrey Bailey, Rachele Bigi, Blossom Damania, Dirk P. Dittmer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	INK128 Kaposi's sarcoma-associated herpesvirus MLN0128 sapanisertib everolimus lymphoma Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9e5c6d0be51c4fd4bea1e3aa9ddf3942
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spelling	oai:doaj.org-article:9e5c6d0be51c4fd4bea1e3aa9ddf39422021-11-15T15:55:14ZTargeting mTOR with MLN0128 Overcomes Rapamycin and Chemoresistant Primary Effusion Lymphoma10.1128/mBio.02871-182150-7511https://doaj.org/article/9e5c6d0be51c4fd4bea1e3aa9ddf39422019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02871-18https://doaj.org/toc/2150-7511ABSTRACT Primary effusion lymphoma (PEL) is caused by Kaposi’s sarcoma-associated herpesvirus (KSHV). PEL has a highly active mTOR pathway, which makes mTOR a potential therapeutic target. MLN0128 is an ATP-competitive inhibitor of mTOR that has entered clinical trials for solid tumors. Our results demonstrated that MLN0128 has a greater effect on inhibiting proliferation than the allosteric mTOR inhibitor rapamycin. MLN0128 has ∼30 nM 50% inhibitory concentration (IC50) across several PEL cell lines, including PEL that is resistant to conventional chemotherapy. MLN0128 induced apoptosis in PEL, whereas rapamycin induced G1 arrest, consistent with a different mechanism of action. MLN0128 inhibited phosphorylation of mTOR complex 1 and 2 targets, while rapamycin only partially inhibited mTOR complex 1 targets. PEL xenograft mouse models treated with MLN0128 showed reduced effusion volumes in comparison to the vehicle-treated group. Rapamycin-resistant (RR) clones with an IC50 for rapamycin 10 times higher than the parental IC50 emerged consistently after rapamycin exposure as a result of transcriptional adaptation. MLN0128 was nevertheless capable of inducing apoptosis in these RR clones. Our results suggest that MLN0128 might offer a new approach to the treatment of chemotherapy-resistant PEL. IMPORTANCE Primary effusion lymphoma (PEL) is an aggressive and incurable malignancy, which is usually characterized by lymphomatous effusions in body cavities without tumor masses. PEL has no established treatment and a poor prognosis, with a median survival time shorter than 6 months. PEL usually develops in the context of immunosuppression, such as HIV infection or post-organ transplantation. The optimal treatment for PEL has not been established, as PEL is generally resistant to traditional chemotherapy. The molecular drivers for PEL are still unknown; however, PEL displays a constitutively active mammalian target of rapamycin (mTOR) pathway, which is critical for metabolic and cell survival mechanisms. Therefore, the evaluation of novel agents targeting the mTOR pathway could be clinically relevant for the treatment of PEL.Carolina Caro-VegasAubrey BaileyRachele BigiBlossom DamaniaDirk P. DittmerAmerican Society for MicrobiologyarticleINK128Kaposi's sarcoma-associated herpesvirusMLN0128sapanisertibeverolimuslymphomaMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	INK128 Kaposi's sarcoma-associated herpesvirus MLN0128 sapanisertib everolimus lymphoma Microbiology QR1-502
spellingShingle	INK128 Kaposi's sarcoma-associated herpesvirus MLN0128 sapanisertib everolimus lymphoma Microbiology QR1-502 Carolina Caro-Vegas Aubrey Bailey Rachele Bigi Blossom Damania Dirk P. Dittmer Targeting mTOR with MLN0128 Overcomes Rapamycin and Chemoresistant Primary Effusion Lymphoma
description	ABSTRACT Primary effusion lymphoma (PEL) is caused by Kaposi’s sarcoma-associated herpesvirus (KSHV). PEL has a highly active mTOR pathway, which makes mTOR a potential therapeutic target. MLN0128 is an ATP-competitive inhibitor of mTOR that has entered clinical trials for solid tumors. Our results demonstrated that MLN0128 has a greater effect on inhibiting proliferation than the allosteric mTOR inhibitor rapamycin. MLN0128 has ∼30 nM 50% inhibitory concentration (IC50) across several PEL cell lines, including PEL that is resistant to conventional chemotherapy. MLN0128 induced apoptosis in PEL, whereas rapamycin induced G1 arrest, consistent with a different mechanism of action. MLN0128 inhibited phosphorylation of mTOR complex 1 and 2 targets, while rapamycin only partially inhibited mTOR complex 1 targets. PEL xenograft mouse models treated with MLN0128 showed reduced effusion volumes in comparison to the vehicle-treated group. Rapamycin-resistant (RR) clones with an IC50 for rapamycin 10 times higher than the parental IC50 emerged consistently after rapamycin exposure as a result of transcriptional adaptation. MLN0128 was nevertheless capable of inducing apoptosis in these RR clones. Our results suggest that MLN0128 might offer a new approach to the treatment of chemotherapy-resistant PEL. IMPORTANCE Primary effusion lymphoma (PEL) is an aggressive and incurable malignancy, which is usually characterized by lymphomatous effusions in body cavities without tumor masses. PEL has no established treatment and a poor prognosis, with a median survival time shorter than 6 months. PEL usually develops in the context of immunosuppression, such as HIV infection or post-organ transplantation. The optimal treatment for PEL has not been established, as PEL is generally resistant to traditional chemotherapy. The molecular drivers for PEL are still unknown; however, PEL displays a constitutively active mammalian target of rapamycin (mTOR) pathway, which is critical for metabolic and cell survival mechanisms. Therefore, the evaluation of novel agents targeting the mTOR pathway could be clinically relevant for the treatment of PEL.
format	article
author	Carolina Caro-Vegas Aubrey Bailey Rachele Bigi Blossom Damania Dirk P. Dittmer
author_facet	Carolina Caro-Vegas Aubrey Bailey Rachele Bigi Blossom Damania Dirk P. Dittmer
author_sort	Carolina Caro-Vegas
title	Targeting mTOR with MLN0128 Overcomes Rapamycin and Chemoresistant Primary Effusion Lymphoma
title_short	Targeting mTOR with MLN0128 Overcomes Rapamycin and Chemoresistant Primary Effusion Lymphoma
title_full	Targeting mTOR with MLN0128 Overcomes Rapamycin and Chemoresistant Primary Effusion Lymphoma
title_fullStr	Targeting mTOR with MLN0128 Overcomes Rapamycin and Chemoresistant Primary Effusion Lymphoma
title_full_unstemmed	Targeting mTOR with MLN0128 Overcomes Rapamycin and Chemoresistant Primary Effusion Lymphoma
title_sort	targeting mtor with mln0128 overcomes rapamycin and chemoresistant primary effusion lymphoma
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/9e5c6d0be51c4fd4bea1e3aa9ddf3942
work_keys_str_mv	AT carolinacarovegas targetingmtorwithmln0128overcomesrapamycinandchemoresistantprimaryeffusionlymphoma AT aubreybailey targetingmtorwithmln0128overcomesrapamycinandchemoresistantprimaryeffusionlymphoma AT rachelebigi targetingmtorwithmln0128overcomesrapamycinandchemoresistantprimaryeffusionlymphoma AT blossomdamania targetingmtorwithmln0128overcomesrapamycinandchemoresistantprimaryeffusionlymphoma AT dirkpdittmer targetingmtorwithmln0128overcomesrapamycinandchemoresistantprimaryeffusionlymphoma
_version_	1718427234655535104

Targeting mTOR with MLN0128 Overcomes Rapamycin and Chemoresistant Primary Effusion Lymphoma

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