CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Cholangiocarcinoma (CCA) is an aggressive cancer with few treatment options.
• Valosin-containing protein (VCP) is identified as a key dependency in CCA.
• Therapy resistance is a challenge in CCA treatment, partly due to persistent senescent cells.

Purpose of the Study:

• To investigate VCP as a therapeutic target in CCA.
• To evaluate the efficacy of a VCP inhibitor, CB-5339, alone and in combination with senolytic agents.
• To explore a novel therapeutic strategy for CCA.

Main Methods:

• Genome-wide CRISPR-Cas9 screening to identify CCA dependencies.
• Compound screening using VCP inhibitor CB-5339 on patient-derived CCA organoids.
• Combination therapy with CB-5339 and senolytic agents (ABT-263, conatumumab) in vitro and in vivo.
• Clinical analysis of VCP expression in CCA patient samples.

Main Results:

• VCP was identified as a critical dependency in CCA.
• CB-5339 inhibited CCA proliferation by inducing cellular senescence.
• Combination therapy with CB-5339 and senolytic agents demonstrated enhanced tumor suppression.
• VCP overexpression correlated with poor prognosis in CCA patients.

Conclusions:

• Targeting VCP to induce senescence, followed by senolytic clearance, presents a "one-two punch" therapeutic strategy for CCA.
• This approach shows promise for improving treatment outcomes in cholangiocarcinoma.
• VCP inhibition and senolytic therapy offer a novel avenue for CCA treatment.