Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines
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Updated: Jun 17, 2025
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Anne Huber1, Amr H Allam1, Christine Dijkstra1
1Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia.
Abstract:
Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in the glandular epithelium of KrasG12D;Pik3caH1047R or Trp53R172H and/or ablation of Pten or Trp53. We find that KrasG12D;Pik3caH1047R is sufficient to induce adenomas and that lesions progress to carcinoma when also harboring Pten deletions. An additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutant Trp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with the poorer survival of patients with high IL-6 expression, we identify IL-6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer.
Insights
KRAS and PI3K pathway activation with TP53 mutations drive gastric cancer. Mutant TP53 promotes metastasis via an IL-11 to IL-6 switch, identifying IL-6/STAT3 signaling as a therapeutic target in TP53-mutant gastric cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Aberrant activation of KRAS and PI3K pathways, along with TP53 mutations, are common in human gastric cancers.
- The precise sequence and individual contributions of these genetic alterations in gastric cancer development remain unclear.
Purpose of the Study:
- To elucidate the roles of KRAS, PI3K, and TP53 mutations in gastric cancer progression.
- To investigate the impact of Pten ablation on tumor development.
- To identify key signaling pathways driving metastatic disease.
Main Methods:
- Generation of an allelic series of genetically engineered mouse models.
- Conditional expression of KrasG12D, Pik3caH1047R, and Trp53R172H in glandular epithelium.
- Ablation of Pten or Trp53 in combination with oncogenic drivers.
Main Results:
- KrasG12D;Pik3caH1047R initiated adenomas, which progressed to carcinoma with Pten deletion.
- Trp53 alterations (loss or gain-of-function) accelerated tumor progression and metastasis.
- Metastatic progression involved a switch in interleukin dependency (IL-11 to IL-6) driven by mutant TP53.
- STAT3 signaling was crucial for tumor development, with IL-6/STAT3 identified as a vulnerability in TP53-mutant tumors.
Conclusions:
- Combined KRAS and PI3K pathway activation, modulated by TP53 status and Pten loss, drives gastric tumorigenesis and metastasis.
- Mutant TP53 induces an IL-6 dependency critical for metastasis.
- Targeting the IL-6/STAT3 pathway presents a potential therapeutic strategy for TP53-mutant gastric cancer.
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