Mutational analysis of PTEN/PIK3CA/AKT pathway in oral squamous cell carcinoma

Cohen, Yoram; Goldenberg-Cohen, Nitza; Shalmon, Bruria; Shani, Tali; Oren, Shmuel; Amariglio, Ninette; Dratviman‐Storobinsky, Olga; Shnaiderman-Shapiro, Anna; Yahalom, Ran; Kaplan, Ilana; Hirshberg, Abraham

doi:10.1016/j.oraloncology.2011.07.013

Cited by 61 publications

(56 citation statements)

References 37 publications

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“…Loss of PTEN expression may occur by gene methylation, mutations, or posttranslational modifications. 17,33 Curiously, we found a positive association of PTEN expression with p-mTOR expression; tumors in which a high expression of PTEN was noted also had higher coexpression of p-mTOR than tumors with low PTEN expression. In some tumors, the high expression of PTEN may be a biological response to a high p-mTOR expression.…”

Section: Discussionmentioning

confidence: 68%

Phosphorylated mammalian target of rapamycin is associated with an adverse outcome in oral squamous cell carcinoma

Monteiro¹,

Delgado²,

Ricardo³

et al. 2013

Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

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Section: Discussionmentioning

confidence: 68%

Phosphorylated mammalian target of rapamycin is associated with an adverse outcome in oral squamous cell carcinoma

Monteiro¹,

Delgado²,

Ricardo³

et al. 2013

Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

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“…HNSCC lesions harbor activating mutations in PIK3CA (8% to 13%) (24,37–41) encoding the catalytic PI3K-α subunit and oncogenic mutants of the HRAS (4% to 9%) (24,41,42) or KRAS (3% to 7%) genes (41,43–45), collectively referred herein as RAS . As PIK3CA and RAS mutants stimulate mTOR downstream of EGFR, we asked whether their expression is sufficient to confer cetuximab resistance.…”

Section: Resultsmentioning

confidence: 99%

mTOR Co-Targeting in Cetuximab Resistance in Head and Neck Cancers Harboring PIK3CA and RAS Mutations

Wang

Martin

Molinolo

et al. 2014

JNCI: Journal of the National Cancer Institute

100

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BackgroundCetuximab, a monoclonal blocking antibody against the epidermal growth factor receptor EGFR, has been approved for the treatment of squamous cell carcinomas of the head and neck (HNSCC). However, only few patients display long-term responses, prompting the search for cetuximab resistance mechanisms and new therapeutic options enhancing cetuximab effectiveness.MethodsCetuximab-sensitive HNSCC cells were retro-engineered to express PIK3CA and RAS oncogenes. These cells and HNSCC cells harboring endogenous PIK3CA and RAS oncogenes were xenografted into mice (n = 10 per group) and studied for their biochemical, antitumor, antiangiogenic, and antilymphangiogenic responses to cetuximab and mTOR targeting agents. All P values are two-sided.ResultsCetuximab treatment of PIK3CA- and RAS-expressing HNSCC xenografts promoted an initial antitumor response, but all tumors relapsed within few weeks. In these tumors, cetuximab did not decrease the activity of mTOR, a downstream signaling target of EGFR, PIK3CA, and RAS. The combined administration of cetuximab and mTOR inhibitors exerted a remarkably increased antitumor activity, particularly in HNSCC cells that are resistant to cetuximab as a single agent. Indeed, cotargeting mTOR together with cetuximab caused a rapid tumor collapse of both PIK3CA- and RAS-expressing HNSCC xenografts (P < .001), concomitant with reduced proliferation (P < .001) and lymphangiogenesis (P < .001).ConclusionThe presence of PIK3CA and RAS mutations and other alterations affecting the mTOR pathway activity in HNSCC could be exploited to predict the potential resistance to cetuximab, and to select the patients that may benefit the most from the concomitant administration of cetuximab and PI3K and/or mTOR inhibitors as a precision molecular therapeutic option for HNSCC patients.

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“…PTEN has been identified as a tumor suppressor and negative regulator of the PI3K/Akt signaling pathway. The PI3K/Akt signaling pathway has been identified as an oncogenic pathway and regulator of numerous cellular processes, including proliferation, cell cycle, migration, invasion and apoptosis (32,33). The results of the present study suggest that OSCC cell proliferation, invasion and apoptosis are associated with expression of PTEN.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of miR-221/222 by a microRNA sponge promotes apoptosis in oral squamous cell carcinoma cells through upregulation of PTEN

et al. 2016

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MicroRNA-221 and microRNA-222 (miR-221/222) have been identified as oncogenes and confirmed to be overexpressed in various types of cancer. However, the regulation mechanism of miR-221/222 in oral squamous cell carcinoma (OSCC) remains to be fully elucidated. Previously, an miR-221/222 sponge was successfully constructed and its effect on the downregulation of miR-221/222 expression was investigated. In the present study, the dual luciferase reporter assay revealed a phosphatase and tensin homolog (PTEN) deletion on chromosome 10 to be a target gene of miR-221/222. It was also demonstrated that miR-221/222 suppression by transfection with an miR-221/222 sponge in vitro resulted in upregulation of PTEN. Notably, the proliferation and invasiveness of the miR-221/222 sponge-transfected cells was significantly inhibited, while apoptosis was promoted, when determined by Cell Counting Kit-8, Transwell assays and flow cytometry. The results of the present study prove that miR-221/222 may downregulate the expression of PTEN in OSCC cells and function as oncogenes, providing a novel insight into the underlying mechanism of OSCC tumorigenesis. The present study suggests that upregulating the expression of PTEN by downregulation of miR-221/222 may be a potential treatment for OSCC.

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Mutational analysis of PTEN/PIK3CA/AKT pathway in oral squamous cell carcinoma

Cited by 61 publications

References 37 publications

Phosphorylated mammalian target of rapamycin is associated with an adverse outcome in oral squamous cell carcinoma

Phosphorylated mammalian target of rapamycin is associated with an adverse outcome in oral squamous cell carcinoma

mTOR Co-Targeting in Cetuximab Resistance in Head and Neck Cancers Harboring PIK3CA and RAS Mutations

Downregulation of miR-221/222 by a microRNA sponge promotes apoptosis in oral squamous cell carcinoma cells through upregulation of PTEN

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