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Elevated Type I Interferon Signaling Defines the Proliferative Advantage of ARF and p53 Mutant Tumor Cells
Alex Mabry1,2, Catherine E Kuzmicki1, Angelina O'Brien1
1Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA.
Abstract:
The tumor suppressors p53 and ARF collaborate to prevent unwarranted cell proliferation and as such are two of the most frequently mutated genes in human cancer. Concomitant loss of functional p53 and ARF leads to massive gains in cell proliferation and transformation and is often observed in some of the most aggressive human cancer subtypes. These phenotypic gains are preceded by increased type I interferon (IFN) signaling that involves canonical STAT1 activation and a subsequent IFN-stimulated gene (ISG) signature. Here, we show that cells lacking p53 and ARF require active JAK1 to phosphorylate STAT1 on Y701 to maintain their high rate of proliferation. In fact, the use of selective JAK1 inhibitors ruxolitinib or baricitinib inhibited the induction of ISG's and the proliferation of p53 and ARF deleted cells. We identify a group of solid human tumors that lack functional p53 and ARF, show an expression signature of the upregulated type I IFN response genes, and are sensitive to selective JAK1 inhibitors. These data suggest that the type I IFN response acts as a positive driver of proliferation in the absence of p53 and ARF and, as such, presents itself as a potential therapeutic target in aggressive solid tumors.
Insights
Loss of tumor suppressors p53 and ARF boosts cancer cell proliferation via type I interferon (IFN) signaling. Inhibiting JAK1 blocks this proliferation, offering a new therapeutic strategy for aggressive solid tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The tumor suppressors p53 and ARF are critical in preventing uncontrolled cell growth.
- Loss of both p53 and ARF is common in aggressive human cancers, leading to increased proliferation.
Purpose of the Study:
- To investigate the role of type I interferon (IFN) signaling in p53 and ARF-deficient cancer cells.
- To explore JAK1 as a potential therapeutic target in these cancers.
Main Methods:
- Analyzing p53 and ARF-deficient cells.
- Investigating the role of Janus Kinase 1 (JAK1) in STAT1 phosphorylation.
- Utilizing selective JAK1 inhibitors (ruxolitinib, baricitinib).
- Examining gene expression signatures in human solid tumors.
Main Results:
- Cells lacking p53 and ARF depend on active JAK1 for STAT1 phosphorylation (pSTAT1 Y701) and proliferation.
- JAK1 inhibition suppressed IFN-stimulated gene (ISG) induction and proliferation in these cells.
- A subset of human solid tumors lacking p53/ARF showed upregulated type I IFN response genes and sensitivity to JAK1 inhibitors.
Conclusions:
- Type I IFN signaling drives proliferation in the absence of p53 and ARF.
- JAK1 is essential for this pro-proliferative pathway.
- Targeting JAK1 with inhibitors presents a promising therapeutic avenue for aggressive solid tumors with p53 and ARF loss.
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