Somatic mutations in salivary duct carcinoma and potential therapeutic targets

Khoo, Timothy; Yu, Bing; Smith, Joel; Luk, Peter P.; Selinger, Christina; Mahon, Kate; Kraitsek, Spiridoula; Boyer, Michael; Dinger, Marcel E.; Cowley, Mark J.; O’Toole, Sandra A.; Clark, Jonathan; Gupta, Ruta

doi:10.1016/j.pathol.2016.12.301

Cited by 7 publications

(8 citation statements)

References 20 publications

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“…31,60 In contrast to SDC cells, head and neck squamous cell carcinoma cells with PTEN loss were commonly resistant to pan-PI3K inhibitor, indicating differences in tumor context. 61 Contrary to previous reports of the involvement of HRas proto-oncogene, GTPase (HRAS) gene mutation in one-third of SDCs, [45][46][47]62 we identified no HRAS mutations in the current cohort (Supporting Tables 4 and 5). Together with the lack of cell lines that had mutations of HRAS gene, the current results suggest a minimal functional role for HRAS in SDC tumorigenesis.…”

Section: Discussioncontrasting

confidence: 99%

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

Saintigny

Mitani

Pytynia

et al. 2018

Cancer

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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.

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Section: Discussioncontrasting

confidence: 99%

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

Saintigny

Mitani

Pytynia

et al. 2018

Cancer

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“…Significant efforts have been devoted to survey SDC somatic mutations and identify genetic insults that can be targeted (5)(6)(7)(8)(9)(10)(11). These studies revealed mutations in cancer genes involved in DNA damage, mitogen-activated protein kinase signaling, receptor tyrosine kinase, PI3K-AKT signaling, androgen signaling, histone modifiers, and other categories.…”

Section: Introductionmentioning

confidence: 99%

The molecular landscape and microenvironment of salivary duct carcinoma reveal new therapeutic opportunities

Alame

Cornillot

Cacheux

et al. 2019

Preprint

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AbstractSalivary duct carcinoma (SDC) is a rare and aggressive salivary gland cancer subtype with poor prognosis. The mutational landscape of SDC has been described rather exhaustively; yet, with respect to functional genomics and tumor microenvironment, little is known. In this study, transcriptomics and proteomics were combined to obtain the first characterization of the pathways deregulated in SDC. The data revealed the importance of Notch, TGB-β, and interferon-γ signaling. After associating computational biology, immunohistochemistry, multiplexed immunofluorescence, and digital imaging the first steps towards charting the cellular network within the microenvironment was initiated. According to immune infiltrate, two well-defined groups of tumors were observed, novel SDC immune checkpoints were discovered, and the key role played by macrophages and potentially NK cells in immunosuppression was shown. Furthermore, a clear trend between recurrence-free survival and M2 macrophage abundance was apparent. Independently, a measure of desmoplastic stromal reaction as determined by α-SMA abundance, was also shown. Altogether, these many findings open new perspectives for understanding and treating SDC. Before applying an immunotherapy, classical patient stratification according to immune infiltrate should be taken into account. Moreover, the microenvironment offers new potential targets including macrophages or NK cells, or even fibroblasts or hyaluronic acid. Related therapies that have been developed against, e.g., pancreatic tumors could inspire equivalent therapy for SDC.Additional informationFinancial support: MA (1 grant, GIRCI SOOM API-K 2016-811-DRC-AC), JC (2 grants, Fondation ARC PJA 20141201975, Labex EpiGenMed ANR 10-LABX-0012), AT (2 grants, Gunma University GIAR Research Program for Omics-Based Medical Science, Labex MabImprove ANR 10-LABX-0053 starting grant), ET (1 grant, SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553).No conflict of interest5408 words, 1 table, and 4 figuresStatement of translational relevanceBased on the presence or absence of an immune infiltrate, two groups of SDC were identified. These have the potential to provide a rationale for therapy and clinical trial enrolment. Two novel immune checkpoints that could be targeted were also identified; namely, CTLA-4/CD86 and TIM-3/galectin-9. Both showed the important contribution that macrophages and NK cells have in immunosuppression. Treatments that induce reprogramming or elimination of these cells could be considered. Moreover, the importance of the desmoplastic stroma was stressed. The stroma acts as a physical barrier against therapy suggesting that strategies developed against pancreatic tumors could inspire SDC treatments. For SDC devoid of immune infiltrate, components of the stroma including fibroblasts or hyaluronic acid could be targeted, e.g., in combination with drugs against immune checkpoints or mutated genes. Finally, evidence that Notch and TGF-β signaling are prevalent in SDC was obtained. This translates into additional therapeutic options.

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“…Also, somatic alterations in PIK3CA and HRAS may alter sensitivity to androgen deprivation therapy and trastuzumab but are susceptible to (mechanistic target of rapamycin) and mitogen extracellular signal-regulated kinases inhibitors. 51 BRAF V600E is another novel actionable genetic mutation noted to occur in approximately 7% of SDCa. Multiple clinical trials are testing the mitogen extracellular signal-regulated kinases inhibitors as potential therapy in the BRAF-mutant cancers.…”

Section: Cribriform Adenocarcinoma Of the Tongue And Minor Salivary Gmentioning

confidence: 99%

“…Approximately, 80% of SDCa harbour alterations in pathways that may be susceptible to currently available systemic therapies. Also, somatic alterations in PIK3CA and HRAS may alter sensitivity to androgen deprivation therapy and trastuzumab but are susceptible to (mechanistic target of rapamycin) and mitogen extracellular signal‐regulated kinases inhibitors . BRAF V600E is another novel actionable genetic mutation noted to occur in approximately 7% of SDCa.…”

Section: Investigationsmentioning

confidence: 99%

Primary salivary gland malignancies: a review of clinicopathological evolution, molecular mechanisms and management

Badlani

Gupta

Balasubramanian

et al. 2017

ANZ Journal of Surgery

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Salivary gland cancers are a complex group of tumours with variations in location, type and grade, all of which influence their biological behaviour. The understanding of salivary gland pathology has evolved at the molecular level in the last decade leading to identification of distinct entities, development of improved methods of diagnosis as well as identifying therapeutic targets for selected high-grade tumours. This article focuses on these advances and their impact on the management of primary salivary gland cancers.

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Somatic mutations in salivary duct carcinoma and potential therapeutic targets

Cited by 7 publications

References 20 publications

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

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

The molecular landscape and microenvironment of salivary duct carcinoma reveal new therapeutic opportunities

Primary salivary gland malignancies: a review of clinicopathological evolution, molecular mechanisms and management

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