Related Experiment Video
Updated: Jan 28, 2026
A Semi-Quantitative Drug Affinity Responsive Target Stability DARTS assay for studying Rapamycin/mTOR interaction
Published on: August 27, 2019
Targeting mTOR with MLN0128 Overcomes Rapamycin and Chemoresistant Primary Effusion Lymphoma
Carolina Caro-Vegas1,2, Aubrey Bailey1, Rachele Bigi1
1UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
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.
Insights
MLN0128 effectively inhibits primary effusion lymphoma (PEL) cell proliferation and induces apoptosis, even in chemotherapy-resistant cases. This mTOR inhibitor shows promise as a novel therapeutic for aggressive PEL, outperforming rapamycin.
Area of Science:
- Oncology
- Virology
- Pharmacology
Background:
- Primary effusion lymphoma (PEL) is an aggressive, incurable malignancy linked to Kaposi's sarcoma-associated herpesvirus (KSHV).
- PEL is characterized by body cavity effusions, poor prognosis, and resistance to conventional chemotherapy, often occurring in immunocompromised individuals.
- The mammalian target of rapamycin (mTOR) pathway is constitutively active in PEL, presenting a potential therapeutic target.
Purpose of the Study:
- To evaluate MLN0128, an ATP-competitive mTOR inhibitor, as a potential treatment for primary effusion lymphoma (PEL).
- To compare the efficacy of MLN0128 against rapamycin, an allosteric mTOR inhibitor, in PEL models.
- To investigate MLN0128's activity against chemotherapy-resistant PEL and rapamycin-resistant clones.
Main Methods:
- Assessed MLN0128's inhibitory concentration (IC50) and effects on proliferation and apoptosis in PEL cell lines.
- Compared MLN0128's mechanism of action with rapamycin, including effects on mTOR complex 1 and 2 targets.
- Utilized PEL xenograft mouse models to evaluate MLN0128's in vivo efficacy and assessed MLN0128's activity against rapamycin-resistant PEL clones.
Main Results:
- MLN0128 demonstrated potent inhibition of PEL cell proliferation (∼30 nM IC50) and induced apoptosis, unlike rapamycin which caused G1 arrest.
- MLN0128 inhibited both mTOR complex 1 and 2 targets, while rapamycin only partially inhibited mTOR complex 1.
- In vivo studies showed reduced effusion volumes in MLN0128-treated mice; MLN0128 effectively induced apoptosis in rapamycin-resistant PEL clones.
Conclusions:
- MLN0128 exhibits superior efficacy over rapamycin in inhibiting PEL cell proliferation and inducing apoptosis.
- MLN0128 demonstrates significant activity against chemotherapy-resistant PEL and rapamycin-resistant variants.
- MLN0128 represents a promising novel therapeutic strategy for treating aggressive and treatment-resistant primary effusion lymphoma.
Related Concept Videos
03:48Behavior of Gas Molecules: Molecular Diffusion, Mean Free Path, and Effusion
01:25Pleural Effusion I: Introduction
There are two main types of pleural effusion: transudative and exudative. They are differentiated using Light's...
01:28Pleural Effusion II: Symptoms and Management
A pleural effusion is the abnormal collection of fluid between the parietal and visceral pleura layers of tissue that form the lining of the lungs and chest cavity. It can occur independently or due to surrounding parenchymal diseases, such as infection, malignancy, or inflammatory conditions.
Clinical Manifestations:
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:22PI3K/mTOR/AKT Signaling Pathway
01:22Bioavailability Enhancement: Determination and Conceptual Approaches in Overcoming Bioavailability Problems