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Updated: May 23, 2025

Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols
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Loss of JAK1 Function Causes G2/M Cell Cycle Defects Vulnerable to Kif18a Inhibition

Vanessa Kelley1,2, Marta Baro1, William Gasperi1

  • 1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06510 USA.

Biorxiv : the Preprint Server for Biology
|March 10, 2025
PubMed

Insights

Janus Kinase 1 (JAK1) drives tumor cell radiosensitivity in head and neck squamous cell carcinoma (HNSCC). Inhibiting JAK1 or Kif18a enhances radiation efficacy by disrupting cell cycle arrest and mitotic progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Head and neck squamous cell carcinoma (HNSCC) exhibits resistance to DNA damage therapies.
  • Understanding resistance mechanisms is crucial for improving cancer treatment efficacy.

Purpose of the Study:

  • To identify novel biological mechanisms driving therapeutic resistance in HNSCC.
  • To explore strategies for overcoming radioresistance by targeting cell cycle regulation.

Main Methods:

  • Parallel pooled genetic CRISPR-Cas9 screening was employed in high-risk HNSCC subtypes.
  • JAK1 knockout (KO) and inhibition (using abrocitinib) were assessed for effects on DNA damage response.
  • Cell cycle progression, mitotic defects, and DNA damage markers (e.g., micronuclei) were analyzed.
  • Kif18a inhibition was evaluated as a strategy to enhance radiation efficacy.

Main Results:

  • JAK1 was identified as a key driver of tumor cell radiosensitivity, alongside ATM, DNAPK, and NFKB signaling.
  • JAK1 KO enhanced DNA damage-induced G2 arrest, increasing cell survival.
  • JAK1 inhibition and KO reduced radiation-induced micronuclei formation.
  • Loss of JAK1 function impaired PLK1 and AURKA activation, leading to mitotic defects.
  • Kif18a inhibition was shown to exacerbate mitotic stress and enhance radiation efficacy.

Conclusions:

  • JAK1 plays a critical role in regulating HNSCC radiosensitivity by influencing G2 arrest and mitotic progression.
  • Targeting JAK1 or Kif18a represents a promising strategy to overcome therapeutic resistance to DNA damage in HNSCC.
  • Modulating cell cycle checkpoints offers a novel approach to enhance the effectiveness of radiotherapy.

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