Frequent PTEN loss and differential HER2/PI3K signaling pathway alterations in salivary duct carcinoma: Implications for targeted therapy
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Updated: Feb 4, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Pierre Saintigny1,2,3, Yoshitsugu Mitani4, Kristen B Pytynia5
1Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
Background:
Patients with advanced primary and recurrent salivary duct carcinoma (SDC), a rare and lethal malignancy, have limited therapeutic options. Novel small-molecule agents aimed at targeting critical signaling associated with SDC tumorigenesis may lead to new therapeutic options for patients with these tumors. The human epidermal growth factor receptor 2 (HER2)/phosphoinositide 3-kinase (PI3K) axis, an important oncogenic pathway, has been targeted for therapy in several solid tumors. Currently, little is known about the role and clinical implications of alterations of the HER2/PI3K pathway in patients with SDC.
Methods:
The authors investigated the clinicopathologic features, genetic alterations, and expression of key members of the HER2/PI3K pathway in 43 primary tumors and conducted in vitro functional and targeted drug-response analyses on cell lines derived from salivary epithelial carcinomas.
Results:
In primary tumors, loss of phosphatase and tensin homolog (PTEN) expression was identified in 22 of 43 tumors (51%), overexpression of HER2 was observed in 12 of 43 tumors (28%), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations were identified in 12 of 43 tumors (28%). Phosphorylated protein kinase B (p-AKT) was highly expressed in most tumors. Most tumors (70%) displayed mutually exclusive alterations of PI3K members, whereas 8 tumors (19%) had 2 or more concurrent abnormalities. In vitro studies demonstrated a direct association between PTEN loss and PI3K pathway activation and evidence of response to combined PI3Kα and PI3Kβ and/or pan-PI3K inhibitors.
Conclusions:
The current analyses reveal frequent PTEN loss and mutually exclusive alterations of key PI3K pathway members in SDC and demonstrate in vitro evidence of a response to pan-PI3K inhibitors. These results provide a framework for a biomarker-based substratification of patients with SDC in future targeted therapy. Cancer 2018;124:3523-32. © 2018 American Cancer Society.
Insights
Salivary duct carcinoma (SDC) often shows loss of phosphatase and tensin homolog (PTEN) and alterations in the phosphoinositide 3-kinase (PI3K) pathway. These findings suggest potential efficacy of pan-PI3K inhibitors for targeted SDC therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Salivary duct carcinoma (SDC) is a rare, aggressive cancer with limited treatment options.
- The human epidermal growth factor receptor 2 (HER2)/phosphoinositide 3-kinase (PI3K) pathway is implicated in various solid tumors.
- Understanding HER2/PI3K pathway alterations in SDC is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate clinicopathologic features and genetic alterations of the HER2/PI3K pathway in SDC.
- To assess the expression of key pathway members and their clinical implications.
- To evaluate in vitro responses to targeted inhibitors.
Main Methods:
- Analysis of 43 primary SDC tumors for genetic alterations and protein expression.
- In vitro functional studies using SDC cell lines.
- Targeted drug-response assays with PI3K pathway inhibitors.
Main Results:
- PTEN loss (51%), HER2 overexpression (28%), and PIK3CA mutations (28%) were frequent.
- Most tumors (70%) had mutually exclusive PI3K pathway alterations.
- In vitro studies showed PTEN loss correlated with PI3K pathway activation and sensitivity to pan-PI3K inhibitors.
Conclusions:
- Frequent PTEN loss and PI3K pathway alterations characterize SDC.
- In vitro data support the potential of pan-PI3K inhibitors for SDC treatment.
- Biomarker-based stratification of SDC patients may guide future targeted therapy.
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