2. Academic Validation
  3. Loss of JAK1 Function Causes G2/M Cell Cycle Defects Vulnerable to Kif18a Inhibition

Loss of JAK1 Function Causes G2/M Cell Cycle Defects Vulnerable to Kif18a Inhibition

  • bioRxiv. 2025 Feb 24:2025.02.19.638911. doi: 10.1101/2025.02.19.638911.
Vanessa Kelley 1 2,  Marta Baro 1,  William Gasperi 1,  Nicholas Ader 3 4,  Hannah Lea 1 5,  Hojin Lee 1,  Chatchai Phoomak 1 6,  Lilian Kabeche 7,  Megan King 4,  Joseph Contessa 1 2
Affiliations

Affiliations

  • 1 Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06510 USA.
  • 2 Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510 USA.
  • 3 Department of Biology, University of North Carolina Greensboro, Greensboro, NC 27412 USA.
  • 4 Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510 USA.
  • 5 Program in Translational Biomedicine, Yale University School of Medicine, New Haven, CT 06510 USA.
  • 6 Department of Biology, Chulalongkorn University, Bangkok 10330, Thailand.
  • 7 Department Molecular Biophysics and Biomedicine, Yale University School of Medicine, New Haven, CT 06510 USA.
PMID: 40060568 DOI: 10.1101/2025.02.19.638911
Abstract

To gain insight into biological mechanisms that cause resistance to DNA damage, we performed parallel pooled genetic CRISPR-Cas9 screening for survival in high risk HNSCC subtypes. Surprisingly, and in addition to ATM, DNAPK, and NFKB signaling, JAK1 was identified as a driver of tumor cell radiosensitivity. Knockout of JAK1 in HNSCC increases cell survival by enhancing the DNA damage-induced G2 arrest, and both knockout and JAK1 inhibition with abrocitinib prevent subsequent formation of radiation-induced micronuclei. Loss of JAK1 function does not affect canonical CDK1 signaling but does reduce activation of PLK1 and AURKA, kinases that regulate both G2 and M phase progression. Correspondingly, JAK1 KO was found to cause mitotic defects using both EdU labeling and live cell imaging techniques. Given this insight, we evaluated Kif18a inhibition as an approach to exacerbate mitotic stress and enhance the efficacy of radiation. These studies establish Kif18a inhibition as a novel strategy to counteract therapeutic resistance to DNA damage mediated by G2 cell cycle arrest.

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