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Background <p>Synthetic lethal interactions are attractive therapeutic candidates as they enable selective targeting of cancer cells in which somatic alterations have disrupted one member of a synthetic lethal gene pair while leaving normal tissues untouched, thus minimising off-target toxicity. Despite this potential, the number of well-established and validated synthetic lethal gene pairs is modest.</p> Results <p>We generate a dual-guide CRISPR/Cas9 Library and analyse 472 predicted synthetic lethal pairs in 27 cancer cell Lines from melanoma, pancreatic and lung cancer Lineages. We report a robust collection of 117 genetic interactions within and across cancer types and explore their candidacy as therapeutic targets. We show that SLC25A28 is an attractive target since its synthetic lethal paralog partner SLC25A37 is homozygously deleted pan-cancer. We generate knockout mice for <i>Slc25a28</i> revealing that, except for cataracts in some mice, these animals are normal; suggesting inhibition of SLC25A28 is unlikely to be associated with profound toxicity.</p> Conclusions <p>We provide and validate an extensive collection of synthetic lethal interactions across cancer types.</p>

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A compendium of synthetic lethal gene pairs defined by extensive combinatorial pan-cancer CRISPR screening

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月18日

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  • Victoria Harle,
  • Victoria Offord,
  • Birkan Gökbağ,
  • Lazaros Fotopoulos,
  • Thomas Williams,
  • Diana Alexander,
  • Ishan Mehta,
  • Nicola A. Thompson,
  • Rebeca Olvera-León,
  • Stefan Peidli,
  • Vivek Iyer,
  • Emanuel Gonçalves,
  • Narod Kebabci,
  • Barbara De Kegel,
  • Joris van de Haar,
  • Lang Li,
  • Colm J. Ryan,
  • David J. Adams

摘要

Background

Synthetic lethal interactions are attractive therapeutic candidates as they enable selective targeting of cancer cells in which somatic alterations have disrupted one member of a synthetic lethal gene pair while leaving normal tissues untouched, thus minimising off-target toxicity. Despite this potential, the number of well-established and validated synthetic lethal gene pairs is modest.

Results

We generate a dual-guide CRISPR/Cas9 Library and analyse 472 predicted synthetic lethal pairs in 27 cancer cell Lines from melanoma, pancreatic and lung cancer Lineages. We report a robust collection of 117 genetic interactions within and across cancer types and explore their candidacy as therapeutic targets. We show that SLC25A28 is an attractive target since its synthetic lethal paralog partner SLC25A37 is homozygously deleted pan-cancer. We generate knockout mice for Slc25a28 revealing that, except for cataracts in some mice, these animals are normal; suggesting inhibition of SLC25A28 is unlikely to be associated with profound toxicity.

Conclusions

We provide and validate an extensive collection of synthetic lethal interactions across cancer types.