Therapeutic implication of mTORC2 in oral squamous cell carcinoma

Naruse, Tomofumi; Yanamoto, Souichi; Okuyama, Kazuaki; Yamashita, Kentaro; Omori, Keisuke; Nakao, Yuji; Yamada, Shin‐ichi; Umeda, Masahiro

doi:10.1016/j.oraloncology.2016.12.012

Cited by 16 publications

(11 citation statements)

References 31 publications

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“…RICTOR was expressed variably across the tumor tissues surveyed, with the majority of samples having strong and complete expression of RICTOR (score of 3), consistent with other studies that have found positive RICTOR IHC staining in the majority of HNSCC cases examined ( Fig. 2A; Naruse et al, 2017). RICTOR was detected in both the cytoplasm and the nucleus in some cases (Rosner and Hengstschlager, 2008).…”

Section: Relation Between Rictor Expression Clinicopathological Varisupporting

confidence: 88%

“…Elevated expression of RICTOR is known to promote increased mTORC2 activity, and RICTOR is essential for the catalytic activity of mTOR (Laugier et al, 2015). Previous studies have similarly found oral squamous cell carcinomas to exhibit positive RICTOR IHC staining in the majority of cases surveyed (68%) (Naruse et al, 2017). We observed genomic aberrations in RICTOR and PIK3CA to significantly co-occur in HNSCC tumors; as patients with PIK3CA aberrations are thought to be optimal candidates for PI3K inhibition therapy, the prevalence of RICTOR amplifications or RNA overexpression in this cohort may have therapeutic implications (Gkountakos et al, 2018).…”

Section: Discussionmentioning

confidence: 76%

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Disruption of the RICTOR/mTORC2 complex enhances the response of head and neck squamous cell carcinoma cells to PI3K inhibition

et al. 2019

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Phosphoinositide 3‐kinase (PI3K) is aberrantly activated in head and neck squamous cell carcinomas (HNSCC) and plays a pivotal role in tumorigenesis by driving Akt signaling, leading to cell survival and proliferation. Phosphorylation of Akt Thr308 by PI3K‐PDK1 and Akt Ser473 by mammalian target of rapamycin complex 2 (mTORC2) activates Akt. Targeted inhibition of PI3K is a major area of preclinical and clinical investigation as it reduces Akt Thr308 phosphorylation, suppressing downstream mTORC1 activity. However, inhibition of mTORC1 releases feedback inhibition of mTORC2, resulting in a resurgence of Akt activation mediated by mTORC2. While the role of PI3K‐activated Akt signaling is well established in HNSCC, the significance of mTORC2‐driven Akt signaling has not been thoroughly examined. Here we explore the expression and function of mTORC2 and its obligate subunit RICTOR in HNSCC primary tumors and cell lines. We find RICTOR to be overexpressed in a subset of HNSCC tumors, including those with PIK3CA or EGFR gene amplifications. Whereas overexpression of RICTOR reduced susceptibility of HNSCC tumor cells to PI3K inhibition, genetic ablation of RICTOR using CRISPR/Cas9 sensitized cells to PI3K inhibition, as well as to EGFR inhibition and cisplatin treatment. Further, mTORC2 disruption led to reduced viability and colony forming abilities of HNSCC cells relative to their parental lines and induced loss of both activating Akt phosphorylation modifications (Thr308 and Ser473). Taken together, our findings establish RICTOR/mTORC2 as a critical oncogenic complex in HNSCC and rationalize the development of an mTORC2‐specific inhibitor for use in HNSCC, either combined with agents already under investigation, or as an independent therapy.

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Section: Relation Between Rictor Expression Clinicopathological Varisupporting

confidence: 88%

Section: Discussionmentioning

confidence: 76%

Disruption of the RICTOR/mTORC2 complex enhances the response of head and neck squamous cell carcinoma cells to PI3K inhibition

et al. 2019

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“…In the present study, both cetuximab and alpelisib inhibited cell invasion and migration potential, and their combined treatment resulted in additive inhibition of OSCC migration and invasion potential compared with that in either agent alone. In our previous study the inhibition of the PI3K downstream pathway decreased the migration and invasion ability in the HSC-3 cell line (29). Therefore, combined treatment with alpelisib and cetuximab was effective in OSCC invasion in vitro.…”

Section: Discussionmentioning

confidence: 80%

Selective inhibition of PI3K110α as a novel therapeutic strategy for cetuximab‑resistant oral squamous cell carcinoma

et al. 2020

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High expression of the 110 kDa catalytic subunit of the class IA PI3K (PI3Kp110α) may play an important role in cetuximab resistance exhibited by both colorectal cancer and head and neck squamous cell carcinoma. Therefore, the present study aimed to examine the association between the expression of proteins in the PI3Kp110α pathway and cetuximab resistance, and the antitumor effects of alpelisib (PI3K inhibitor) and cetuximab in oral squamous cell carcinoma (OSCC) cells. The association between PI3Kp110α protein expression levels and the tumor response to cetuximab was determined using immunohistochemistry. OSCC cells were treated with alpelisib, cetuximab, or in combination, and the effects were examined in vitro and in vivo. PI3Kp110α protein expression was significantly associated with the tumor response to cetuximab (P<0.05) and 1-year progression-free survival and overall survival (P<0.05). Combined treatment of alpelisib and cetuximab resulted in enhanced antitumor effects in vitro compared with either agent administered alone. In particular, the expression level of N-cadherin, an epithelial-mesenchymal transition-related protein, was decreased, suggesting that the invasion potential of cetuximab-resistant cells decreased. Furthermore, the expression of proteins in the PI3K pathway were decreased in tumors from mice with OSCC xenografts treated with alpelisib and cetuximab in combination. These results indicate that novel regimens of systemic therapy (such as chemotherapy), with combinations of cetuximab and alpelisib, may be beneficial for patients with cetuximab-resistant OSCC.

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“…Examples of the first generation include rapamycin and its analogs, while the second generation includes AZD8055, Torin1, PP242, and PP30. Until recently, several inhibitors targeting mTOR had been studied for their efficacy in tumor therapy; among these, Torin 1 and Torin 2 are new generation mTOR inhibitors demonstrated to be effective in several cancer types [49,50,51,52,53,54]. Little information is available in the literature about their activity on immune cells; it seems that healthy CD4+ lymphocytes are not affected during treatment for acute T cell leukemia [55].…”

Section: Discussionmentioning

confidence: 99%

mTOR Links Tumor Immunity and Bone Metabolism: What are the Clinical Implications?

Irelli

Sirufo

Scipioni

et al. 2019

IJMS

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Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) plays a crucial role in the control of cellular growth, proliferation, survival, metabolism, angiogenesis, transcription, and translation. In most human cancers, alterations to this pathway are common and cause activation of other downstream signaling pathways linked with oncogenesis. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both tumor immunity and angiogenesis. Inflammation is a hallmark of cancer, playing a central role in the tumor dynamics, and immune cells can exert antitumor functions or promote the growth of cancer cells. In this context, mTOR may regulate the activity of macrophages and T cells by regulating the expression of cytokines/chemokines, such as interleukin (IL)-10 and transforming growth factor (TGF-β), and/or membrane receptors, such as cytotoxic T-Lymphocyte protein 4 (CTLA-4) and Programmed Death 1 (PD-1). Furthermore, inhibitors of mammalian target of rapamycin are demonstrated to actively modulate osteoclastogenesis, exert antiapoptotic and pro-differentiative activities in osteoclasts, and reduce the number of lytic bone metastases, increasing bone mass in tumor-bearing mice. With regard to the many actions in which mTOR is involved, the aim of this review is to describe its role in the immune system and bone metabolism in an attempt to identify the best strategy for therapeutic opportunities in the metastatic phase of solid tumors.

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Therapeutic implication of mTORC2 in oral squamous cell carcinoma

Cited by 16 publications

References 31 publications

Disruption of the RICTOR/mTORC2 complex enhances the response of head and neck squamous cell carcinoma cells to PI3K inhibition

Disruption of the RICTOR/mTORC2 complex enhances the response of head and neck squamous cell carcinoma cells to PI3K inhibition

Selective inhibition of PI3K110α as a novel therapeutic strategy for cetuximab‑resistant oral squamous cell carcinoma

mTOR Links Tumor Immunity and Bone Metabolism: What are the Clinical Implications?

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