Overexpression of PIK3CA in head and neck squamous cell carcinoma is associated with poor outcome and activation of the YAP pathway

García‐Escudero, Ramón; Segrelles, Carmen; Dueñas, Marta; Pombo, María Teresa; Ballestı́n, Claudio; Alonso-Riaño, Marina; Nenclares, Pablo; Álvarez-Rodríguez, Roberto; Aniceto, Gregorio Sánchez; Ruiz-Alonso, A.; López-Cedrún, José Luís; Paramio, Jesús M.; Lorz, Corina

doi:10.1016/j.oraloncology.2018.02.014

Cited by 59 publications

(50 citation statements)

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“…Activating mutations of PIK3CA have been found in approximately 20% of HNSCC, and increase in PIK3CA copy number and/or overexpression is present in up to 40% of the cases [3]. Overexpression of the PIK3CA gene is a poor prognosis factor in HNSCC and is associated with the activation of YAP [24]. In contrast to other tumors, mutations in EGFR are not frequent in HNSCC (≤5%) [3].…”

Section: Molecular Alterations In Hnsccmentioning

confidence: 99%

“…Additionally, two upstream regulators of this pathway are frequently altered in HNSCC, namely FAT1 and PIK3CA. Inactivation of FAT1 (deletion, truncating mutations) or activation of PIK3CA (overexpression) are associated with YAP-dependent transcriptional activation in HNSCC [24,27]. The precise molecular mechanisms that contribute to tumor development in the context of FAT1 functional loss or PIK3CA overexpression are not fully understood (Figure 2).…”

Section: The Hippo-yap Pathway In Hnsccmentioning

confidence: 99%

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Hippo Pathway and YAP Signaling Alterations in Squamous Cancer of the Head and Neck

Santos-de-Frutos

Segrelles

Lorz

2019

JCM

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Head and neck cancer affects the upper aerodigestive tract and is the sixth leading cancer worldwide by incidence and the seventh by cause of death. Despite significant advances in surgery and chemotherapy, molecularly targeted therapeutic options for this type of cancer are scarce and long term survival rates remain low. Recently, comprehensive genomic studies have highlighted the most commonly altered genes and signaling pathways in this cancer. The Hippo-YAP pathway has been identified as a key oncogenic pathway in multiple tumors. Expression of genes controlled by the Hippo downstream transcriptional coactivators YAP (Yes-associated protein 1) and TAZ (WWTR1, WW domain containing transcription regulator 1) is widely deregulated in human cancer including head and neck squamous cell carcinoma (HNSCC). Interestingly, YAP/TAZ signaling might not be as essential for the normal homeostasis of adult tissues as for oncogenic growth, altogether making the pathway an amenable therapeutic target in cancer. Recent advances in the role of Hippo-YAP pathway in HNSCC have provided evidence that genetic alterations frequent in this type of cancer such as PIK3CA (phosphatidylinositide 3-kinase catalytic subunit alpha) overexpression or FAT1 (FAT atypical cadherin 1) functional loss can result in YAP activation. We discuss current therapeutic options targeting this pathway which are currently in use for other tumor types.

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Section: Molecular Alterations In Hnsccmentioning

confidence: 99%

Section: The Hippo-yap Pathway In Hnsccmentioning

confidence: 99%

Hippo Pathway and YAP Signaling Alterations in Squamous Cancer of the Head and Neck

Santos-de-Frutos

Segrelles

Lorz

2019

JCM

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“…[ 169 ] Recent evidence suggests that PI3K‐Akt signaling also inhibits the Hippo pathway to promote YAP/TAZ activation to drive cell proliferation and malignancy. [ 99,115,170‐178 ] Importantly, further work is necessary to identify the molecular mechanism by which PI3K‐Akt signaling inhibits the Hippo pathway. In addition, while PI3K‐Akt signaling appears necessary to promote YAP/TAZ activation, it is apparently not sufficient, as cells also require mechanical stimulation or other additional inputs to activate YAP/TAZ.…”

Section: Introductionmentioning

confidence: 99%

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

2020

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The transcriptional co-activators YAP (or YAP1) and TAZ (or WWTR1) are frequently activated during the growth and progression of many solid tumors, including lung, colorectal, breast, pancreatic, and liver carcinomas as well as melanoma and glioma. YAP/TAZ bind to TEAD-family co-activators to drive cancer cell survival, proliferation, invasive migration, and metastasis. YAP/TAZ activation may also confer resistance to chemotherapy, radiotherapy, or immunotherapy. YAP-TEAD cooperates with the RAS-induced AP-1 (FOS/JUN) transcription factor to drive tumor growth and cooperates with MRTF-SRF to promote activation of cancer-associated fibroblasts, matrix stiffening, and metastasis. The key upstream repressor of YAP/TAZ activation is the Hippo (MST1/2-LATS1/2) pathway and the key upstream activators are mechanically induced Integrin-SRC and E-cadherin-AJUBA/TRIP6/LIMD1, growth factor induced PI3K-AKT, and inflammation-induced G-protein coupled receptor (GPCR) signals, all of which antagonize the Hippo pathway. In this review, strategies to target YAP/TAZ activity in cancer are discussed along with the prospects for synergy with established pillars of cancer therapy.

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“…Recently, YAP was also shown to undergo monomethylation by SET1A, which in turn blocks its cytoplasmic export and ultimately promotes tumorigenesis [11]. As part of a crosstalk with other signaling pathways, YAP nuclear localization and activation is induced by PI3 kinase (PI3K) and phosphoinositide-dependent kinase (PDK1), which work in concert by inhibiting the Hippo pathway, leading to poor prognosis in patients [12,13]. While discussed elsewhere, it is important to note that other signaling pathways, including WNT and G protein-coupled signaling, as well as processes like metabolism and mechanotransduction also regulate YAP/TAZ [14].…”

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confidence: 99%

Hippo Pathway in Cancer: Aberrant Regulation and Therapeutic Opportunities

Calses¹,

Crawford²,

Lill³

et al. 2019

Trends in Cancer

320

220

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The Hippo pathway remains a central focus in both basic and translational research and is a key modulator of developmental biology. Dysregulation of the pathway is associated with a plethora of human cancers and there are multiple efforts to target key components of the pathway for disease intervention. In this review, we briefly highlight the latest research advances around the core components of the Hippo pathway in cancer. More specifically, we discuss several genetic aberrations of these factors as mechanisms for the development of cancers, including genetic amplification, deletion, and gene fusions. Additionally, we highlight the role of the Hippo pathway in cancer therapy resistance and tumor immunogenicity. Last, we summarize the ongoing efforts to target the pathway in cancers. The Hippo Pathway The Hippo pathway is a highly conserved signaling pathway across higher-order vertebrates that modulates key target genes to regulate a multitude of biological processes including cellular proliferation, survival, differentiation, cellular fate determination, organ size, and tissue homeostasis (Figure 1). At the core of the pathway are serine/threonine kinases, sterile 20-like kinase 1/2 (MST1/2), and large tumor suppressor 1/2 (LATS1/2). Recently, MAP4K and TAOK kinases have been shown to directly phosphorylate LATS1/2, thus acting in parallel with MST1/2 [1]. These kinases, along with the adaptor proteins, Salvador homolog 1 (SAV1) and MOB kinase activator 1A/B (MOB1A/B), phosphorylate and inhibit downstream effector proteins, Yesassociated protein (YAP1), and its paralog transcriptional coactivator with PDZ-binding motif (TAZ) (also known as WWTR1) and sequestrates them in the cytoplasm by binding to 14-3-3 proteins [2]. Notably, the tumor suppressor neurofibromin 2 (NF2) (also known as Merlin) participates upstream of these kinases to inhibit YAP and TAZ activity by promoting the activation of the pathway. Additional phosphorylation of YAP/TAZ leads to proteasome-mediated degradation facilitated by binding to β-TrCP [3,4]. Such regulation prevents YAP/TAZ from accumulating in the nucleus and from binding to a family of sequence-specific transcription factors called TEA DNA-binding proteins (TEAD1-4) that mediate proliferative and prosurvival genes such as CTGF, CRY61, BIRC5, ANKRD1, and AXL (Figure 2). Besides TEADs, YAP/TAZ also cooperates with RUNT-related transcription factors (RUNX1 and 2), T-box transcription factor 5 (TBX5), and SMADs as among others [2,5]. Hippo Pathway Deregulation in Cancer Overexpression of Hippo Pathway Effector Proteins Aberration of the Hippo pathway is associated with the hallmarks of oncogenesis and, more recently, has been linked to other cellular processes such as regulation of T cell functionality [6]. These hallmarks include the induction of hyperproliferation, cellular invasion, and metastasis, as well as a role in cancer cell maintenance and chemotherapeutic resistance mechanisms. Analysis of over 9000 tumors showed that YAP and TAZ are frequently amplified in head and nec...

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Overexpression of PIK3CA in head and neck squamous cell carcinoma is associated with poor outcome and activation of the YAP pathway

Cited by 59 publications

References 46 publications

Hippo Pathway and YAP Signaling Alterations in Squamous Cancer of the Head and Neck

Hippo Pathway and YAP Signaling Alterations in Squamous Cancer of the Head and Neck

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

Hippo Pathway in Cancer: Aberrant Regulation and Therapeutic Opportunities

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