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Ref Type Journal Article
PMID (30289966)
Authors Saintigny P, Mitani Y, Pytynia KB, Ferrarotto R, Roberts DB, Weber RS, Kies MS, Maity SN, Lin SH, El-Naggar AK
Title Frequent PTEN loss and differential HER2/PI3K signaling pathway alterations in salivary duct carcinoma: Implications for targeted therapy.
Journal Cancer
Vol 124
Issue 18
Date 2018 09 15
URL
Abstract Text 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.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
PTEN L152P missense loss of function PTEN L152P lies within the phosphatase tensin-type domain of the Pten protein (UniProt.org). L152P is associated with decreased Pten expression and increased Akt phosphorylation in cultured cells (PMID: 30289966), and results in reduced phosphatase activity in a yeast assay (PMID: 29706350).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN L152P PTEN neg salivary gland carcinoma sensitive Alpelisib + AZD8186 Preclinical - Cell culture Actionable In a preclinical study, combination of Piqray (Alpelisib) and AZD8186 inhibited Akt phosphorylation and proliferation of salivary ductal carcinoma cells harboring PTEN L152P and loss of Pten protein expression in culture (PMID: 30289966). 30289966
PTEN L152P PTEN neg salivary gland carcinoma resistant AZD8186 Preclinical - Cell culture Actionable In a preclinical study, salivary ductal carcinoma cells harboring PTEN L152P and loss of Pten protein expression were resistant to AZD8186-induced inhibition of Akt phosphorylation and proliferation in culture (PMID: 30289966). 30289966
PTEN L152P PTEN neg salivary gland carcinoma resistant GSK2636771 Preclinical - Cell culture Actionable In a preclinical study, salivary ductal carcinoma cells harboring PTEN L152P and loss of Pten protein expression were resistant to GSK2636771-induced inhibition of proliferation in culture (PMID: 30289966). 30289966
PTEN L152P PTEN neg salivary gland carcinoma resistant Alpelisib Preclinical - Cell culture Actionable In a preclinical study, salivary ductal carcinoma cells harboring PTEN L152P and loss of Pten protein expression were resistant to Piqray (Alpelisib)-induced inhibition of Akt phosphorylation and proliferation in culture (PMID: 30289966). 30289966
PTEN L152P PTEN neg salivary gland carcinoma sensitive Pictilisib Preclinical - Cell culture Actionable In a preclinical study, Pictilisib (GDC-0941) inhibited Akt phosphorylation and proliferation of salivary ductal carcinoma cells harboring PTEN L152P and loss of Pten protein expression in culture (PMID: 30289966). 30289966