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New target: Researchers identify pancreatic cancer resistance mechanism
Date:6/19/2014

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Yap1 is involved in gene transcription the activation of genes by proteins that bind to the gene's DNA in its promoter region but does not itself bind to DNA. As a co-activator, it works through other transcription factors.

Enabled by genome-scale unbiased and molecular analyses, the researchers found that Yap1 forms a complex with Tead2, one of its known partners, and then works with E2F, another transcription factor. Together, they activate a cell cycle and DNA replication program to support tumor survival and growth.

"With Kras turned off, Yap1 can recreate this transcription program involving cell cycle and DNA replication machinery that is normally controlled by Kras," Yao said.

Yap1 and human tumors Recent classification of pancreatic cancer based on gene transcription profiles identified a subtype that is not dependent on Kras. These so-called quasimesenchymal tumors have a poor prognosis.

The team confirmed that Yap1 is highly expressed in these tumor cell lines and that knocking down Yap1 suppressed proliferation of these cells.

Yap1 is known to be involved in cell proliferation, a cellular conversion known as epithelial-to-mesenchymal transition, cancer invasion and metastasis and has been found amplified in liver, oral squamous cell and esophageal cancers as well as in medulloblastoma.

While Yap1 drives tumor recurrence and progression, Kapoor said evidence shows that it is insufficient to drive initial formation of pancreatic cancer.

Yap1, like Kras, is not presently targetable with a drug. The researchers note that small molecules targeting Yap1 have stalled liver cancer progression in a mouse model and might eventually prove to work in Yap1-dependent cancer. Clinical trials of this approach are years away.

Future studies by the team include understanding Yap1's role in quasimesenchymal pancreatic cancer and exploring potential signaling connections between Kras a
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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert  

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