MEK Is a Therapeutic and Chemopreventative Target in Squamous Cell Carcinoma

Adelmann, Charles H.; Truong, Kimberly; Liang, Roger J.; Bansal, Varun; Gandee, Leah; Saporito, Rachael C.; Lee, Woojin; Du, Lili; Nicholas, Courtney; Napoli, Marco; Mino, Barbara; South, Andrew P.; Proby, Charlotte M.; Leigh, Irene M.; Coarfa, Cristian; Flores, Elsa R.; Tsai, Kenneth Y.

doi:10.1016/j.jid.2016.05.110

Cited by 13 publications

(23 citation statements)

References 15 publications

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“…Similarly, a core set of 196 genes was found to be differentially expressed between AK and cSCC and gene set enrichment analysis indicated a key role for MAPK pathway in cSCC compared to AK [ 42 ]. Consistent with this, more recently it has been shown that inhibition of MEK causes senescence, but not apoptosis, in cSCC cell lines and reduces tumour growth in vivo [ 43 ]. Several lines of evidence also indicate that activation of the enzymes belonging to the phosphoinositide 3-kinase (PI3K) family is involved in cSCC carcinogenesis (as discussed in more detail below).…”

Section: Overview Of Cscc Carcinogenesissupporting

confidence: 53%

Phosphoinositide 3-Kinase-Dependent Signalling Pathways in Cutaneous Squamous Cell Carcinomas

Janus

O'Shaughnessy

Harwood

et al. 2017

Cancers

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Cutaneous squamous cell carcinoma (cSCC) derives from keratinocytes in the epidermis and accounts for 15–20% of all cutaneous malignancies. Although it is usually curable by surgery, 5% of these tumours metastasise leading to poor prognosis mostly because of a lack of therapies and validated biomarkers. As the incidence rate is rising worldwide it has become increasingly important to better understand the mechanisms involved in cSCC development and progression in order to develop therapeutic strategies. Here we discuss some of the evidence indicating that activation of phosphoinositide 3-kinases (PI3Ks)-dependent signalling pathways (in particular the PI3Ks targets Akt and mTOR) has a key role in cSCC. We further discuss available data suggesting that inhibition of these pathways can be beneficial to counteract the disease. With the growing number of different inhibitors currently available, it would be important to further investigate the specific contribution of distinct components of the PI3Ks/Akt/mTOR pathways in order to identify the most promising molecular targets and the best strategy to inhibit cSCC.

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Section: Overview Of Cscc Carcinogenesissupporting

confidence: 53%

Phosphoinositide 3-Kinase-Dependent Signalling Pathways in Cutaneous Squamous Cell Carcinomas

Janus

O'Shaughnessy

Harwood

et al. 2017

Cancers

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“…There are a number of publications using the UT-SCC HNSCC lines, which include five primary cSCC lines (UT-SCC-12A, 91, 105, 111, 118) and three metastatic cSCC lines (UT-SCC-7, 59A, 115) [13,14,15], but the characterisation of these lines has not been reported comprehensively. SRB-1 and SRB-12 cell lines were derived from a moderately well-differentiated cSCC [6,16,17], and Colo16 was developed from a metastatic cSCC arising in a chronic burn scar on the leg of a 59-year-old black female [18]; all three have subsequently been used in drug discovery studies [19,20,21,22,23,24,25,26,27]. A model of skin carcinogenesis has been developed using mutant Ras/Cdk4 transfection of normal keratinocytes [28,29]; however, HRas mutations are uncommon in human cSCC.…”

Section: Discussionmentioning

confidence: 99%

“…The effects of mitogen-activated protein kinase kinase (MEK) inhibition on cSCC responses were tested using two MEK inhibitors, trametinib and cobimetinib, in 10 cell lines (including IC1, T2, T3, T8), nine of which responded at high concentrations. However, this sensitivity was not correlated with the mutational status of RAS or epidermal growth factor receptor (EGFR) [27].…”

Section: Discussionmentioning

confidence: 99%

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A Unique Panel of Patient-Derived Cutaneous Squamous Cell Carcinoma Cell Lines Provides a Preclinical Pathway for Therapeutic Testing

Hassan

Purdie

Wang

et al. 2019

IJMS

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Background: Cutaneous squamous cell carcinoma (cSCC) incidence continues to rise with increasing morbidity and mortality, with limited treatment options for advanced disease. Future improvements in targeted therapy will rely on advances in genomic/transcriptomic understanding and the use of model systems for basic research. We describe here the panel of 16 primary and metastatic cSCC cell lines developed and characterised over the past three decades in our laboratory in order to provide such a resource for future preclinical research and drug screening. Methods: Primary keratinocytes were isolated from cSCC tumours and metastases, and cell lines were established. These were characterised using short tandem repeat (STR) profiling and genotyped by whole exome sequencing. Multiple in vitro assays were performed to document their morphology, growth characteristics, migration and invasion characteristics, and in vivo xenograft growth. Results: STR profiles of the cSCC lines allow the confirmation of their unique identity. Phylogenetic trees derived from exome sequence analysis of the matched primary and metastatic lines provide insight into the genetic basis of disease progression. The results of in vivo and in vitro analyses allow researchers to select suitable cell lines for specific experimentation. Conclusions: There are few well-characterised cSCC lines available for widespread preclinical experimentation and drug screening. The described cSCC cell line panel provides a critical tool for in vitro and in vivo experimentation.

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“…The involvement of RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways in cancer has led to the development of several inhibitors that target them [92,93]. In CSCC, a recent in vivo study demonstrated that the inhibition of MEK with trametinib and cobimetinib induces senescence in CSCC cell lines and reduces tumor growth in a mouse model [94]. Moreover, cobimetinib is being studied in combination with atezolizumab, a PD-L1 inhibitor, in metastatic or locally advanced and unresectable CSCCs, and locally advanced CSCCs that are technically resectable but where surgery could produce disfigurement (NCT03108131).…”

Section: Other Targeted Therapies In Csccmentioning

confidence: 99%

Cutaneous Squamous Cell Carcinoma: From Biology to Therapy

Corchado-Cobos

García-Sancha

González-Sarmiento

et al. 2020

IJMS

122

111

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Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and its incidence continues to rise. Although CSCC usually display a benign clinical behavior, it can be both locally invasive and metastatic. The signaling pathways involved in CSCC development have given rise to targetable molecules in recent decades. In addition, the high mutational burden and increased risk of CSCC in patients under immunosuppression were part of the rationale for developing the immunotherapy for CSCC that has changed the therapeutic landscape. This review focuses on the molecular basis of CSCC and the current biology-based approaches of targeted therapies and immune checkpoint inhibitors. Another purpose of this review is to explore the landscape of drugs that may induce or contribute to the development of CSCC. Beginning with the pathogenetic basis of these drug-induced CSCCs, we move on to consider potential therapeutic opportunities for overcoming this adverse effect.

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MEK Is a Therapeutic and Chemopreventative Target in Squamous Cell Carcinoma

Cited by 13 publications

References 15 publications

Phosphoinositide 3-Kinase-Dependent Signalling Pathways in Cutaneous Squamous Cell Carcinomas

Phosphoinositide 3-Kinase-Dependent Signalling Pathways in Cutaneous Squamous Cell Carcinomas

A Unique Panel of Patient-Derived Cutaneous Squamous Cell Carcinoma Cell Lines Provides a Preclinical Pathway for Therapeutic Testing

Cutaneous Squamous Cell Carcinoma: From Biology to Therapy

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