Proteasome Inhibition Sensitizes Liposarcoma to MDM2 Inhibition with Nutlin-3 by Activating the ATF4/CHOP Stress Response Pathway

by Selleckchem | Jul 03 2023

Liposarcoma is the most commonly occurring soft tissue sarcoma and is frequently characterized by amplification of chromosome region 12q13-15 harboring the oncogenes MDM2 and CDK4. This unique genetic profile makes liposarcoma an attractive candidate for targeted therapeutics. While CDK4/6 inhibitors are currently employed for treatment of several cancers, MDM2 inhibitors have yet to attain clinical approval. Here, we report the molecular characterization of the response of liposarcoma to the MDM2 inhibitor nutlin-3. Treatment with nutlin-3 led to upregulation of two nodes of the proteostasis network: the ribosome and the proteasome. CRISPR/Cas9 was used to perform a genome-wide loss of function screen that identified PSMD9, which encodes a proteasome subunit, as a regulator of response to nutlin-3. Accordingly, pharmacological studies with a panel of proteasome inhibitors revealed strong combinatorial induction of apoptosis with nutlin-3. Mechanistic studies identified activation of the ATF4/CHOP stress response axis as a potential node of interaction between nutlin-3 and the proteasome inhibitor carfilzomib. CRISPR/Cas9 gene editing experiments confirmed that ATF4, CHOP, and the BH3-only protein, NOXA, are all required for nutlin-3 and carfilzomib-induced apoptosis. Furthermore, activation of the unfolded protein response using tunicamycin and thapsigargin was sufficient to activate the ATF4/CHOP stress response axis and sensitize to nutlin-3. Finally, cell line and patient-derived xenograft models demonstrated combinatorial effects of treatment with idasanutlin and carfilzomib on liposarcoma growth in vivo. Together, these data indicate that targeting of the proteasome could improve the efficacy of MDM2 inhibitors in liposarcoma.

Comments:

The given passage highlights a study on the molecular characterization of liposarcoma, a type of soft tissue sarcoma. It focuses on the potential use of an MDM2 inhibitor called nutlin-3 as a targeted therapeutic for liposarcoma. The study reports that liposarcoma frequently exhibits amplification of chromosome region 12q13-15, which contains the oncogenes MDM2 and CDK4. This genetic profile makes liposarcoma a promising candidate for targeted therapies.

The researchers found that treatment with nutlin-3 resulted in the upregulation of two components of the proteostasis network: the ribosome and the proteasome. To further investigate the response of liposarcoma to nutlin-3, a genome-wide loss of function screen was conducted using CRISPR/Cas9 gene editing. This screen identified PSMD9, a gene encoding a proteasome subunit, as a regulator of the response to nutlin-3.

To explore potential combinatorial approaches, the researchers performed pharmacological studies with a panel of proteasome inhibitors. They observed a strong induction of apoptosis when nutlin-3 was combined with proteasome inhibitors. Further mechanistic studies revealed that the ATF4/CHOP stress response axis may play a role in the interaction between nutlin-3 and the proteasome inhibitor carfilzomib.

CRISPR/Cas9 gene editing experiments confirmed that ATF4, CHOP, and the BH3-only protein NOXA are all necessary for the induction of apoptosis by the combination of nutlin-3 and carfilzomib. Additionally, the activation of the unfolded protein response using tunicamycin and thapsigargin was found to activate the ATF4/CHOP stress response axis and sensitize liposarcoma cells to nutlin-3.

The researchers also tested the effects of combining idasanutlin, another MDM2 inhibitor, with carfilzomib in cell line and patient-derived xenograft models. The results demonstrated combinatorial effects on the growth of liposarcoma in vivo.

In conclusion, the study suggests that targeting the proteasome, in combination with MDM2 inhibitors like nutlin-3 or idasanutlin, could enhance the efficacy of these inhibitors in treating liposarcoma. By understanding the molecular interactions and signaling pathways involved, this research provides insights into potential therapeutic strategies for liposarcoma patients.