2307P - Loss of CYP2D6 activity sensitizes liver cancer cells to chemotherapy

Background

Loss of heterozygosity (LOH) is a frequent event in cancer, that is caused by larger chromosomal deletions in cancer cells due to genetic instability [TS1] (Mertens et al., 1997). Thus heterozygous individuals become hemi- or homozygous for certain genes, which might change the phenotype of a cancer cell compared to normal cells (Muller et al., 2012), (Dey et al., 2017). This change might create an opportunity to selectively target cancer cells while sparing normal cells ( Rendo et al., 2020).

Methods

To find potential drug targets, data from the 1000 Genomes project was analyzed to identify prevalent constitutional loss-of-function (LoF) SNPs in coding regions causing truncating or splice site mutations with allele frequency >0.5[TS1] [NR2] %, heterozygosity between 10% and 90% of potential relevance in cancer cells. The drug metabolic gene CYP2D6 was selected and isogenic cell models were established in HEK293T and HepG2 cells. A chemical library of a total of 525 compounds was screened using HEK293T cells harboring a functional or loss-of-function CYP2D6 enzyme. Final hits with LoF-selective toxicity were confirmed on the HepG2 cell model and patient-derived hepatocellular carcinoma organoids.

Results

We identified 60 genes with prevalent constitutional LoF variants and the CYP2D6 enzyme was selected for further work due to its well known drug metabolic activity and the high frequency of 22q13 loss in cancers (Mertens et al., 1997). We observed a consistent pattern of responses to Rucaparib, the known CYP2D6 substrate (Zhao, Long and Wang, 2022), on both established HEK293T and HepG2 cell models, suggesting the robustness of our cell models. Three compounds with selective toxicity towards HepG2 and HEK293 cells lacking CYP2D6 activity were identified. One of them is currently available for use in clinical oncology and further confirmed on the patient-derived hepatocellular carcinoma organoids.

Conclusions

LOH in CYP2D6 gene can potentially guide drug use in cancer precision medicine and merits further clinical evaluation.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Cancerfonden.

Disclosure

All authors have declared no conflicts of interest.