Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer	124	18	2018 09 15	3693-3705	Cancer

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	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	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	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
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