Frequent PTEN loss and differential HER2/PI3K signaling pathway alterations in salivary duct carcinoma: Implications for targeted therapy

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 in patients with these tumors. The HER2/PI3K axis, an important oncogenic pathway, has been targeted for therapy in several solid tumors. Currently, little is known on the role and clinical implications of alterations of the HER2/PI3K pathway in SDC. METHODS We investigated the clinicopathologic, 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 on cell lines derived from salivary epithelial carcinomas. RESULTS In primary tumors, loss of PTEN expression was found in 51% (22/43), overexpression of HER2 was observed in 28% (12/43) and PIK3CA mutations were identified in 28% (12/43) of tumors. Phospho-AKT (p-AKT) was highly expressed in most tumors. The majority of tumors (70%) displayed mutually exclusive alterations of PI3K members, while eight (19%) tumors had two or more concurrent abnormalities. In vitro studies demonstrated direct association between PTEN loss and PI3K pathway activation and evidence of response to combined PI3Kα and β and/or pan-PI3K inhibitors. CONCLUSIONS Our study reveals frequent PTEN loss and mutually exclusive alterations of key PI3K pathway members in SDCs and demonstrates in vitro evidence for response to pan-PI3K inhibitors. The study provides a framework for biomarker based sub-stratification of SDC patients’ in future targeted therapy.

Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling

“…Several studies have reported frequent loss of PTEN expression, detected via IHC or FISH analysis, in up to 51% of SDC . In head and neck squamous cell carcinoma, tumor cells with PTEN loss were shown to be commonly resistant to pan‐PI3K inhibitors; however, in vitro studies have shown promising results for targeted PI3K therapy in SDC cells . Finally, the discovery of a TBL1XR1‐PIK3CA fusion, which has been reported to result in overexpression of the complete PIK3CA protein, in one of our cases further supports the important role of PIK3CA in the oncogenesis of SDC …”

“…Besides PIK3CA mutations, loss of PTEN activates the PI3K pathway and thus may represent another potential target. Several studies have reported frequent loss of PTEN expression, detected via IHC or FISH analysis, in up to 51% of SDC . In head and neck squamous cell carcinoma, tumor cells with PTEN loss were shown to be commonly resistant to pan‐PI3K inhibitors; however, in vitro studies have shown promising results for targeted PI3K therapy in SDC cells .…”

“…Despite some headway in targeted therapy for SDC, neither anti‐HER2 nor anti‐androgen therapies have been standardized or clinically validated. In addition, mechanisms of resistance to HER2‐based treatments and ADT may hinder its clinical benefit in some patients . For instance, alterations in phosphoinositide 3‐kinase (PI3K) signaling, either by PIK3CA mutation or PTEN loss, may be involved in resistance to HER2‐targeted therapy .…”

“…In addition, mechanisms of resistance to HER2‐based treatments and ADT may hinder its clinical benefit in some patients . For instance, alterations in phosphoinositide 3‐kinase (PI3K) signaling, either by PIK3CA mutation or PTEN loss, may be involved in resistance to HER2‐targeted therapy . Additionally, the discovery of constitutively active AR splice variants, notably AR splice variant‐7 (AR‐V7), which are implicated in resistance to ADT in prostate cancer, has led to the discovery of these variants in SDC specimens as well .…”

“…14,15 For instance, alterations in phosphoinositide 3-kinase (PI3K) signaling, either by PIK3CA mutation or PTEN loss, may be involved in resistance to HER2-targeted therapy. 15 Additionally, the discovery of constitutively active AR splice variants, notably AR splice variant-7 (AR-V7), which are implicated in resistance to ADT in prostate cancer, has led to the discovery of these variants in SDC specimens as well. 14,[16][17][18] A small study conducted by Cappelletti et al 16 suggests that the presence of AR-V7 in SDC cells may likewise affect response to ADT, but this requires more extensive investigation.…”