Splice-switch oligonucleotide-based combinatorial platform prioritizes synthetic lethal targets CHK1 and BRD4 against...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• MYC deregulation is a key driver in hepatocellular carcinoma (HCC), but targeted therapies have limited success.
• Synthetic lethality presents a promising strategy for treating MYC-deregulated tumors by exploiting specific vulnerabilities.
• Prioritizing effective synthetic lethal targets in HCC remains a challenge.

Purpose of the Study:

• To develop and validate a platform for rapidly identifying and prioritizing synthetic lethal targets in MYC-deregulated HCC.
• To investigate the therapeutic potential of targeting CHK1 and BRD4 in combination for HCC treatment.

Main Methods:

• Utilized splice-switch oligonucleotide (SSO) technology combined with the quadratic phenotypic optimization platform (QPOP) for target interaction analysis.
• Disrupted functional expression of potential targets in combinatorial tests to rank synthetic lethality.
• Validated findings using pharmacological inhibitors in patient-derived HCC organoid models.

Main Results:

• SSO-QPOP analysis identified simultaneous attenuation of CHK1 and BRD4 as a specific and effective combination for MYC-deregulated HCC.
• This combination successfully suppressed HCC progression in vitro.
• Pharmacological inhibition of CHK1 and BRD4 demonstrated synergistic effects in HCC organoid models with high MYC deregulation.

Conclusions:

• The SSO-QPOP platform is effective for prioritizing synthetic lethality targets in drug development.
• Combined targeting of CHK1 and BRD4 shows significant therapeutic potential for MYC-driven HCC.
• This approach offers a new avenue for treating a challenging subset of liver cancer.