Identifying Synthetic Lethal Targets

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A number of different technologies are being used to screen for synthetic lethal combinations, including small interfering RNA (siRNA) screens, small molecule screening in haploid human cells, and exploiting CRISPR-Cas9 based knock-out/knock-in strategies.

From these screening studies, new synthetic lethality targets have been identified, including POLQ (Polθ) and RNASEH2B.

POLQ is required for micro-homology mediated end joining (MMEJ), and it is upregulated and acts as a backup double-strand break repair pathway in HRD. In cancer cells lacking HRR, POLQ-inhibition results in synthetic lethality, via a mechanism that is distinct from PARP inhibition [1-3]. To date POLQ deficiency has been shown to be synthetic lethal with several other cellular pathways, including BRCA, ATM, Ku, 53BP1 and FA pathway mutations [3].

Loss of RNASEH2B in metastatic prostate cancer and chronic lymphocytic leukemia increases PARP-trapping DNA lesions, offering another therapeutic target based on synthetic lethality [4].

See the DDR Compounds in Development  section for more information.

References

  1. Ceccaldi R, Liu JC, Amunugama R et al. Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair. Nature 2015; 518: 258-262.
  2. Mateos-Gomez PA, Gong F, Nair N et al. Mammalian polymerase theta promotes alternative NHEJ and suppresses recombination. Nature 2015; 518: 254-257.
  3. Gourley C, Balmana J, Ledermann JA et al. Moving from PARP Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy. J Clin Oncol 2019; doi: 10.1200/JCO.1218.02050. [Epub ahead of print].
  4. Zimmermann M, Murina O, Reijns MAM et al. CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions. Nature 2018; 559: 285-289.
Last update: 25 July 2019