Advancing Liver Cancer Precision Medicine with TARGET-SL
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Background and Aims
A major goal of personalised liver oncology is the ability to make targeted predictions about cancer-specific toxicity, however there are limited methods available. To address this, we validated the performance of our bioinformatics framework, TARGET-SL, through ex vivo drug screening.
Methods
Using TARGET-SL we predicted gain of function (GOF), loss of function (LOF) and synthetic lethal (SL) genetic events, and corresponding drug candidates. We validated drug predictions across hepatocellular carcinoma (HCC) cell lines, and a cohort of HCC and cholangiocarcinoma (CCA) patient-derived organoids (PDOs).
Results
For HCC cells and PDOs we found 37.5% and 25% of the respective selected compounds induced unique target-specific growth inhibition based on genetic biomarkers, suggesting novel biomarker-driven drug sensitivities.
Conclusions
Our analyses demonstrate TARGET-SL’s potential to enhance personalized drug screening for liver cancer, by focusing on genetically informed targets. This will reduce experimental costs and accelerate the pace of therapeutic discovery.
Impact and Implications
Primary liver cancer (PLC) is a cancer with poor prognosis, and current therapies increase survival only for a minority of patients. Through the application of TARGET-SL we can predict, for each patient, the essential genes and corresponding small molecule inhibitors. These data support further investigation in larger patient cohorts and offer the possibility to specify new small molecule inhibitors and to repurpose current drugs for PLC treatment.
Graphical Abstract
Highlights
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TARGET-SL can predict gene and drug sensitivities for cell lines and patient-derived organoids
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This may reduce drug screening costs and accelerate the pace of therapeutic discovery.
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TARGET-SL may assist in the repurposing of current drugs and their rapid translation for primary liver cancer
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TARGET-SL is tumour-type agnostic, and therefore may have application in other cancers with poor prognosis
