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CDKN2A-Inactivated Pancreatic Ductal Adenocarcinoma Exhibits Therapeutic Sensitivity to Paclitaxel: A Bioinformatics
Jiunn-Chang Lin1,2,3, Tsang-Pai Liu1,2,3,4,5, Pei-Ming Yang3,6,7,8
1Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, Taipei 10449, Taiwan.
Abstract:
The mutation of cyclin dependent kinase inhibitor 2A (CDKN2A) is frequently found in pancreatic ductal adenocarcinoma (PDAC). However, its prognostic and therapeutic roles in PDAC have not been extensively investigated yet. In this study, we mined and integrated the cancer genomics and chemogenomics data to investigate the roles of CDKN2A genetic alterations in PDAC patients' prognosis and treatment. We found that functional CDKN2A inactivation caused by mutations and deep deletions predicted poor prognosis in PDAC patients. CDKN2A inactivation was associated with the upregulation of genes related to estrogen response, which can be overcome by CDKN2A restoration. Chemosensitivity profiling of PDAC cell lines and patient-derived organoids found that CDKN2A inactivation was associated with the increased sensitivity to paclitaxel and SN-38 (the active metabolite of irinotecan). However, only paclitaxel can mimic the effect of CDKN2A restoration, and its drug sensitivity was correlated with genes related to estrogen response. Therefore, our study suggested that CDKN2A-inactivated PDAC patients could benefit from the precision treatment with paclitaxel, whose albumin-stabilized nanoparticle formulation (nab-paclitaxel) has been approved for treating PDAC.
Insights
Cyclin-dependent kinase inhibitor 2A (CDKN2A) inactivation predicts poor prognosis in pancreatic cancer. Restoring CDKN2A or using paclitaxel may improve outcomes for affected patients.
Area of Science:
- Oncology
- Genomics
- Cancer Therapeutics
Background:
- Cyclin-dependent kinase inhibitor 2A (CDKN2A) alterations are common in pancreatic ductal adenocarcinoma (PDAC).
- The prognostic and therapeutic implications of CDKN2A mutations in PDAC remain underexplored.
Purpose of the Study:
- To investigate the impact of CDKN2A genetic alterations on PDAC patient prognosis.
- To explore the therapeutic potential of targeting CDKN2A-inactivated PDAC.
Main Methods:
- Integrated analysis of cancer genomics and chemogenomics data from PDAC patients.
- Functional assessment of CDKN2A inactivation on gene expression and drug sensitivity.
- Chemosensitivity profiling using PDAC cell lines and patient-derived organoids.
Main Results:
- Functional CDKN2A inactivation (mutations, deletions) correlates with poor prognosis in PDAC.
- CDKN2A inactivation is linked to upregulated estrogen response genes, which can be reversed by CDKN2A restoration.
- PDAC with CDKN2A inactivation shows increased sensitivity to paclitaxel and SN-38.
- Paclitaxel treatment mimics CDKN2A restoration effects, with sensitivity linked to estrogen response pathways.
Conclusions:
- CDKN2A inactivation serves as a prognostic marker for poor outcomes in PDAC.
- Restoring CDKN2A function or utilizing paclitaxel offers potential therapeutic strategies for CDKN2A-inactivated PDAC.
- Paclitaxel, particularly nab-paclitaxel, may be a precision treatment for PDAC patients with CDKN2A inactivation.
