Potential Drug Target Identified in Mouse Pancreatic Cancer Model

Cancer researchers studying pancreatic cancer (pancreatic ductal adenocarcinoma or PDAC) have identified Yes-associated protein (YAP) as a potential drug target whose inhibition would block the activity of the KRAS oncogene.

PDAC is an aggressive cancer with poor survival rates that frequently carries an oncogenic KRAS mutation. The protein product of the normal KRAS (Kirsten rat sarcoma viral oncogene) gene performs an essential function in normal tissue signaling, and the mutation of a KRAS gene is an essential step in the development of many cancers. A single amino acid substitution is responsible for the activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas, and colorectal carcinoma.

YAP-1 is a transcriptional coactivator and its proliferative and oncogenic activity is driven by its association with the TEAD family of transcription factors, which upregulate genes that promote cell growth and inhibit apoptosis. Two splice isoforms of the YAP gene product were initially identified, named YAP1-1 and YAP1-2, which differed by the presence of an extra 38 amino acids that encoded the WW domain. Apart from the WW domain, the modular structure of YAP1 contains a proline-rich region at the very amino terminus, which is followed by a TID (TEAD transcription factor interacting domain). Next, following a single WW domain, which is present in the YAP1-1 isoform, and two WW domains, which are present in the YAP1-2 isoform, there is the SH3-BM (Src Homology 3 binding motif). Following the SH3-BM is a TAD (transcription activation domain) and a PDZ domain-binding motif (PDZ-BM).

Investigators at Georgetown University (Washington DC, USA) worked with several different mouse models that had been genetically engineered to have specific KRAS mutations with or without an additional mutation in the p53 gene.

Based on the prior observation that the abundance of YAP mRNA, which encodes Yap, a protein regulated by the Hippo pathway during tissue development and homeostasis, was increased in human PDAC tissue compared with that in normal pancreatic epithelia, the investigators blocked YAP gene activity in the KRAS mutant mice.

They reported in the May 6, 2014, online edition of the journal Science Signaling that when YAP was deleted from the pancreas in these mouse models, the progression of early neoplastic lesions to PDAC was halted without affecting normal pancreatic development and endocrine function. Thus, while suppressing YAP did not prevent pancreatic cancer from first developing, it stopped any further growth.

"We believe this is the true Achilles heel of pancreatic cancer, because knocking out YAP crushes this really aggressive cancer. This appears to be the critical switch that promotes cancer growth and progression," said senior author Dr. Chunling Yi, assistant professor of oncology at Georgetown University. "The KRAS mutation uses YAP to make cancer cells grow, so shutting down YAP defuses the mutated gene's activity."

The investigators showed that YAP was critically required for the proliferation of mutant KRAS or KRAS/p53 neoplastic pancreatic ductal cells in culture and for their growth and progression to invasive PDAC in mice. "KRAS and p53 are two of the most mutated genes in human cancers, so our hope is that a drug that inhibits YAP will work in pancreatic cancer patients — who have both mutations — and in other cancers with one or both mutations," said Dr. Yi.

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