Targeting THOC2-Mediated mRNA Export Induces PARP Inhibitor Vulnerability in DNA Repair-Competent Hepatocellular...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Hepatocellular carcinoma (HCC) presents limited therapeutic options due to low mutation rates in DNA repair genes.
• Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective in tumors with DNA repair defects, but their utility in HCC is restricted.
• Enhanced DNA repair capacity in HCC limits the efficacy of conventional treatments.

Purpose of the Study:

• To identify novel regulators of DNA damage response (DDR) in hepatocellular carcinoma (HCC).
• To investigate the role of THO complex component 2 (THOC2) in DDR and its potential as a therapeutic target.
• To explore strategies for overcoming PARPi resistance in HCC.

Main Methods:

• Proteomic analysis of two independent HCC cohorts (n=260).
• Investigated THOC2's role in mRNA nuclear export of DDR and proliferation-related genes.
• Assessed the synergistic effect of THOC2 knockdown and PARPi (Olaparib) on HCC cell lines and tumor growth.

Main Results:

• THOC2 was identified as a master regulator of DDR through mRNA nuclear export control.
• THOC2 overexpression correlated with poor HCC patient survival and increased DDR gene expression.
• THOC2 knockdown induced synthetic lethality with PARPi, significantly reducing Olaparib efficacy and suppressing tumor growth.

Conclusions:

• THOC2 is a prognostic biomarker and therapeutic target for hepatocellular carcinoma (HCC).
• Targeting mRNA transport offers a novel strategy to modulate DDR and overcome PARPi resistance.
• This study expands the concept of synthetic lethality beyond genetic defects to include post-transcriptional regulation in cancer therapy.