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Schlafen 11 (SLFN11) Kills Cancer Cells Undergoing Unscheduled Re-replication

Junko Murai1,2,3,4, Michele Ceribelli5, Haiqing Fu1

  • 1Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

Molecular Cancer Therapeutics
|May 22, 2023
PubMed

Insights

Schlafen 11 (SLFN11) is a predictive biomarker for cancer drugs. New research shows SLFN11 inhibits unscheduled re-replication caused by pevonedistat, enhancing anticancer efficacy and suggesting SLFN11 as a biomarker for pevonedistat treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Schlafen 11 (SLFN11) is a key predictive biomarker and molecular sensor for various anticancer drugs, including topoisomerase, PARP, replication inhibitors, and platinum derivatives.
  • Expanding the therapeutic targets and drug spectrum associated with SLFN11 is crucial for advancing cancer treatment strategies.

Purpose of the Study:

  • To identify novel drugs and pathways that target SLFN11 by conducting a high-throughput screen.
  • To investigate the mechanism by which pevonedistat and AHPN/CD437 interact with SLFN11 and influence cancer cell viability.
  • To establish SLFN11 as a predictive biomarker for pevonedistat in cancer therapy.

Main Methods:

  • A high-throughput screen of 1,978 oncology-focused compounds was performed using isogenic cell pairs proficient and deficient in SLFN11.
  • Compounds inducing selective killing of SLFN11-proficient cells were identified, including known DNA-targeting agents, pevonedistat, and AHPN/CD437.
  • SLFN11 recruitment to chromatin and its role in regulating unscheduled re-replication upon pevonedistat treatment were analyzed.

Main Results:

  • Twenty-nine hit compounds selectively killed SLFN11-proficient cells, including the neddylation inhibitor pevonedistat and the DNA polymerase α inhibitor AHPN/CD437.
  • Pevonedistat and AHPN/CD437 induced SLFN11 chromatin recruitment, with pevonedistat showing a delayed recruitment (24 hours) compared to other agents (4 hours).
  • SLFN11 inhibited pevonedistat-induced unscheduled re-replication, enhancing anticancer efficacy, and a positive correlation between SLFN11 expression and pevonedistat sensitivity was observed across multiple cancer cell databases.

Conclusions:

  • SLFN11 functions not only as a sensor for replication stress but also actively inhibits unscheduled re-replication induced by pevonedistat, thereby potentiating its anticancer effects.
  • The findings support SLFN11 as a potential predictive biomarker for pevonedistat, guiding its use in current and future clinical trials.
  • This study expands the known drug targets and pathways influenced by SLFN11, offering new avenues for cancer therapy development.

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