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Updated: Apr 7, 2026
Multianimal Magnetic Resonance Imaging for Tumor Measurements in Pancreatic Cancer Mouse Models
Published on: February 3, 2026
A MEK/PI3K/HDAC inhibitor combination therapy for KRAS mutant pancreatic cancer cells
Irene Ischenko1, Oleksi Petrenko1, Michael J Hayman1
1Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY, USA.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, metastatic disease with limited treatment options. Factors contributing to the metastatic predisposition and therapy resistance in pancreatic cancer are not well understood. Here, we used a mouse model of KRAS-driven pancreatic carcinogenesis to define distinct subtypes of PDAC metastasis: epithelial, mesenchymal and quasi-mesenchymal. We examined pro-survival signals in these cells and the therapeutic response differences between them. Our data indicate that the initiation and maintenance of the transformed state are separable, and that KRAS dependency is not a fundamental constant of KRAS-initiated tumors. Moreover, some cancer cells can shuttle between the KRAS dependent (drug-sensitive) and independent (drug-tolerant) states and thus escape extinction. We further demonstrate that inhibition of KRAS signaling alone via co-targeting the MAPK and PI3K pathways fails to induce extensive tumor cell death and, therefore, has limited efficacy against PDAC. However, the addition of histone deacetylase (HDAC) inhibitors greatly improves outcomes, reduces the self-renewal of cancer cells, and blocks cancer metastasis in vivo. Our results suggest that targeting HDACs in combination with KRAS or its effector pathways provides an effective strategy for the treatment of PDAC.
Insights
Targeting histone deacetylase (HDAC) inhibitors with KRAS pathways offers a promising strategy for pancreatic ductal adenocarcinoma (PDAC) treatment, improving outcomes and blocking metastasis.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Therapeutics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with poor prognosis.
- Metastatic predisposition and therapy resistance in PDAC remain poorly understood.
- KRAS-driven pancreatic carcinogenesis models are crucial for studying PDAC progression.
Purpose of the Study:
- To define subtypes of PDAC metastasis.
- To investigate pro-survival signals and therapeutic responses in different PDAC subtypes.
- To identify effective therapeutic strategies for PDAC.
Main Methods:
- Utilized a mouse model of KRAS-driven pancreatic carcinogenesis.
- Characterized epithelial, mesenchymal, and quasi-mesenchymal PDAC subtypes.
- Assessed the efficacy of KRAS inhibition alone and in combination with HDAC inhibitors.
Main Results:
- Identified distinct PDAC metastatic subtypes with varying KRAS dependencies.
- Demonstrated that KRAS dependency is not constant, with cells shifting between drug-sensitive and tolerant states.
- KRAS pathway inhibition alone showed limited efficacy; combination with HDAC inhibitors improved outcomes, reduced self-renewal, and blocked metastasis.
Conclusions:
- KRAS dependency is dynamic in PDAC, allowing cancer cells to evade therapy.
- Combined targeting of HDACs with KRAS or its effector pathways is a potent strategy for PDAC treatment.
- This combination therapy holds promise for improving patient outcomes in pancreatic cancer.
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