Elevated type I interferon signaling defines the proliferative advantage of ARF and p53 mutant tumor cells

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• The tumor suppressors p53 and ARF are critical in preventing uncontrolled cell growth and are frequently mutated in human cancers.
• Loss of both p53 and ARF function accelerates cell proliferation and transformation, characteristic of aggressive cancer subtypes.
• This aggressive phenotype is associated with elevated type I interferon (IFN) signaling, STAT1 activation, and an IFN-stimulated gene (ISG) signature.

Purpose of the Study:

• To investigate the role of Janus Kinase 1 (JAK1) in mediating the proliferative advantage observed in cells lacking p53 and ARF.
• To determine if JAK1 inhibition can suppress the proliferation of p53 and ARF-deficient cancer cells.
• To identify human solid tumors with a p53/ARF-deficient, type I IFN-high signature that may be sensitive to JAK1 inhibitors.

Main Methods:

• Utilized cell culture models lacking functional p53 and ARF.
• Employed selective JAK1 inhibitors (ruxolitinib, baricitinib) to assess their impact on STAT1 phosphorylation and ISG induction.
• Analyzed gene expression profiles of human solid tumors to identify those with a specific molecular signature.

Main Results:

• Cells deficient in p53 and ARF require active JAK1 for STAT1 phosphorylation at Y701, which drives proliferation.
• Treatment with JAK1 inhibitors ruxolitinib or baricitinib effectively reduced ISG induction and proliferation in these cells.
• A subset of human solid tumors lacking p53 and ARF exhibited upregulated type I IFN response genes and sensitivity to JAK1 inhibitors.

Conclusions:

• The type I IFN response actively promotes proliferation in the context of p53 and ARF loss.
• JAK1 is essential for sustaining the proliferative phenotype driven by type I IFN signaling in p53/ARF-deficient cells.
• Targeting JAK1 with selective inhibitors represents a promising therapeutic strategy for aggressive solid tumors characterized by p53/ARF deficiency and elevated type I IFN signaling.