| Speaker: |
Stephen Pettitt
Institute of Cancer Research, London, UK |
| Title: |
Genetic screens in haploid mouse ES cells to determine mechanisms of drug toxicity and resistance |
| abstract : | The recent isolation of haploid mouse embryonic stem cells (ES cells)
greatly expands the scope of genetic screens in cultured cells. We
have used the piggyBac transposon to mutagenise haploid cells and
identified genetic mechanisms of resistance to drugs, including
6-thioguanine, the toxic antiviral fialuridine and the clinical poly
(ADP-ribose) polymerase (PARP) inhibitor olaparib. We identified Parp1
as the major requirement for olaparib toxicity to normal cells. This
supports the hypothesis that inhibited PARP1 is a component of the
toxic DNA damage lesion. Our results suggest that toxicity to normal
cells in patients treated with PARP inhibitors is likely to be an
on-target effect mediated via PARP1, and also identify PARP1 mutation
as a possible route of resistance to PARP inhibitors in tumours.
Haploid screening will be a powerful way of identifying genetic
determinants of toxicity and resistance to other drugs, and
investigating other phenotypes in ES cells.
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