Abstract:
:The number of individuals who succumb to thyroid cancer has been increasing and those who are refractory to standard care have limited therapeutic options, highlighting the importance of developing new treatments for patients with aggressive forms of the disease. Mutational activation of MAPK signaling, through BRAF and RAS mutations and/or gene rearrangements, and activation of PI3K signaling, through mutational activation of PIK3CA or loss of PTEN, are well described in aggressive thyroid cancer. We previously reported overactivation and overexpression of p21-activated kinases (PAKs) in aggressive human thyroid cancer invasive fronts and determined that PAK1 functionally regulated thyroid cancer cell migration. We reported mechanistic crosstalk between the MAPK and PAK pathways that are BRAF-dependent but MEK independent, suggesting that PAK and MEK inhibition might be synergistic. In the present study, we tested this hypothesis. Pharmacologic inhibition of group I PAKs using two PAK kinase inhibitors, G-5555 or FRAX1036, reduced thyroid cancer cell viability, cell cycle progression and migration and invasion, with greater potency for G-5555. Combination of G-5555 with vemurafenib was synergistic in BRAFV600E-mutated thyroid cancer cell lines. Finally, G-5555 restrained thyroid size of BRAFV600E-driven murine papillary thyroid cancer by >50% (P < 0.0001) and reduced carcinoma formation (P = 0.0167), despite maintenance of MAPK activity. Taken together, these findings suggest both that group I PAKs may be a new therapeutic target for thyroid cancer and that PAK activation is functionally important for BRAFV600E-mediated thyroid cancer development.
journal_name
Endocr Relat Cancerjournal_title
Endocrine-related cancerauthors
Knippler CM,Saji M,Rajan N,Porter K,La Perle KMD,Ringel MDdoi
10.1530/ERC-19-0188subject
Has Abstractpub_date
2019-08-01 00:00:00pages
699-712issue
8eissn
1351-0088issn
1479-6821pii
ERC-19-0188.R1journal_volume
26pub_type
杂志文章abstract::Mouse models of prostate cancer (PCa) are critical for understanding the biology of PCa initiation, progression, and treatment modalities. Here, we summarize recent advances in PCa mouse models that led to new insights into specific gene functions in PCa. For example, the study of transgenic mice with TMPRSS2/ERG, an ...
journal_title:Endocrine-related cancer
pub_type: 杂志文章,评审
doi:10.1530/ERC-12-0285
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journal_title:Endocrine-related cancer
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abstract::The expression of estrogen receptor α (ERα) in breast cancer identifies patients most likely to respond to endocrine treatment. The second ER, ERβ, is also expressed in breast tumors, but its function and therapeutic potential need further study. Although in vitro studies have established that ERβ opposes transcriptio...
journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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abstract::Prostate cancer (PCa) is one of the most common causes of male cancer-related death in Western nations. The cellular response to androgens is mediated via the androgen receptor (AR), a ligand-inducible transcription factor whose dysregulation plays a key role during PCa development and progression following androgen d...
journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
doi:10.1530/ERC-14-0254
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pub_type: 杂志文章,多中心研究,随机对照试验
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
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journal_title:Endocrine-related cancer
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journal_title:Endocrine-related cancer
pub_type: 杂志文章
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