Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• The MYC oncogene is crucial for most tumor progressions but remains undruggable by small molecules.
• Targeting MYC's protein interactions (interactome) offers an alternative strategy for cancer therapy.
• Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options.

Purpose of the Study:

• To identify druggable targets within the MYC interactome for PDAC treatment.
• To investigate the role of MYC binding partners in PDAC progression in vitro and in vivo.
• To explore RUVBL1 and RUVBL2 as potential therapeutic targets in MYC-driven cancers.

Main Methods:

• Construction of a targeted shRNA library for screening MYC binding partners.
• Performing genetic screens in cultured PDAC cells and in mouse tumor models.
• Utilizing the auxin-degron system for targeted protein degradation of RUVBL1 in vivo.

Main Results:

• Many MYC binding partners essential in vitro were dispensable in vivo for PDAC cells.
• The ATPases RUVBL1 and RUVBL2 were identified as essential MYC binding partners in vivo.
• RUVBL1 degradation led to PDAC cell cycle arrest, complete tumor regression in mice, and increased immune infiltration.
• RUVBL1 is critical for MYC-mediated oncogenic and immunoevasive gene expression.

Conclusions:

• PDAC cell dependencies are significantly influenced by the tumor microenvironment, necessitating in vitro and in vivo screening.
• The auxin-degron system is a viable tool for target validation in living mouse models.
• The RUVBL1/2 complex represents a druggable vulnerability, offering a novel pharmaceutical strategy to enhance immunotherapy efficacy in pancreatic cancer.