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Frequent PTEN loss and differential HER2/PI3K signaling pathway alterations in salivary duct carcinoma: Implications for targeted therapy
- Source :
- Cancer. 124:3693-3705
- Publication Year :
- 2018
- Publisher :
- Wiley, 2018.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Cancer Research
biology
business.industry
medicine.medical_treatment
Cancer
medicine.disease
medicine.disease_cause
Salivary duct carcinoma
Targeted therapy
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Oncology
030220 oncology & carcinogenesis
biology.protein
medicine
Cancer research
PTEN
Tensin
Carcinogenesis
business
Protein kinase B
PI3K/AKT/mTOR pathway
Subjects
Details
- ISSN :
- 0008543X
- Volume :
- 124
- Database :
- OpenAIRE
- Journal :
- Cancer
- Accession number :
- edsair.doi...........2e46e7a2843db11a68eb89e25387a8ad