Loss of JAK1 Function Causes G2-M Cell-Cycle Defects Vulnerable to KIF18A Inhibition

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Therapeutic resistance to DNA damage presents a major hurdle in cancer treatment.
• Understanding radioresistance mechanisms is crucial for developing effective combination therapies.

Purpose of the Study:

• To identify novel genetic drivers of radioresistance in head and neck squamous cell carcinoma (HNSCC).
• To explore strategies for enhancing tumor cell sensitivity to radiation therapy.

Main Methods:

• Conducted parallel pooled genetic CRISPR-Cas9 screening in HNSCC subtypes.
• Utilized JAK1 knockout, abrocitinib (kinase inhibitor), EdU labeling, and live cell imaging.
• Investigated the role of kinases PLK1, AURKA, and mitotic kinesin KIF18A.

Main Results:

• Loss of JAK1 was identified as a driver of radioresistance, enhancing G2/M cell cycle arrest and delaying mitotic catastrophe.
• JAK1 deficiency reduced PLK1 and AURKA activation, leading to prolonged metaphase and mitotic slippage.
• Targeting KIF18A with sovilnesib exacerbated mitotic stress and improved radiation efficacy.

Conclusions:

• JAK1 loss confers radioresistance by modulating cell cycle progression and mitotic regulation.
• Inhibition of KIF18A represents a promising strategy to overcome DNA damage-induced cell cycle arrest and sensitize tumors to radiation.