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978 Loss of heterozygosity in CYP2D6 locus sensitises cancer cells to talazoparib
  1. Xiaonan Zhang1,
  2. Natallia Rameika1,
  3. Lei Zhong1,
  4. Veronica Rendo1,
  5. Snehangshu Kundu1,
  6. Ioanna Tsiara1,
  7. Daniel Globisch1,
  8. Tobias Sjöblom1,
  9. Shahed Al Nassralla1,
  10. Sandro Nuciforo2,
  11. Markus Heim2 and
  12. Ivaylo Stoimenov1
  1. 1Uppsala University, Uppsala, Sweden
  2. 2University of Basel, Basel, Switzerland

Abstract

Introduction/Background Loss of heterozygosity (LOH) is a common event driven by genetic instability in cancer cells and large chromosomal losses. As a consequence a non-cancer gene gets lost as a bypass event due to its proximity to cancer gene. If this gene was in heterozygous state in a normal cell, tumour cell might become hemi- or homozygous for that gene and change its phenotype compared to normal cells. This change might enable targeting tumour while sparing normal cells. After our initial proof-of-concept study in colorectal cancer with 8p22 loss (Rendo et al., 2020) we sought to broaden search for other targets for LOH-based therapy.

Methodology To find potential drug targets, data from the 1000 Genomes project was analyzed to identify prevalent constitutional loss-of-function (LoF) variants in coding regions causing truncating or splice site mutations considering allele frequency, heterozygosity and potential relevance in cancer. The drug metabolic gene CYP2D6 was selected. We established isogenic cell models in HEK293T and HepG2 cells, screened chemical library of a total of 525 compounds using HEK293T cells harboring a functional or loss-of-function CYP2D6 enzyme and confirmed screen hits with LoF-selective toxicity on the HepG2 cell model and patient-derived hepatocellular carcinoma organoids and started investigation in ovarian cancer cells

Results We identified 60 genes of potential interest, and CYP2D6 enzyme was selected for further work due to its activity and the high frequency of 22q13 loss in cancers. We observed a consistent selectivity in toxicity of rucaparib on HEK293T and HepG2 cell models. Three compounds, among which talazoparib, with selective toxicity towards HepG2 and HEK293 cells lacking CYP2D6 activity were identified. Talazoparib showed similar pattern on the patient-derived liver cancer organoids. We now evaluate these targets in ovarian cancer.

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

Disclosures No conflict of interest.

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