University of Texas MD Anderson Cancer Center President Ron DePinho, MD, along with two other lead co-authors, recently discovered a mechanism for pancreatic cancer resistance and reported their findings in Cell. “Pancreas cancer remains an intractable disease with limited therapeutic options,” said Dr. DePinho, who also serves as a professor of Cancer Biology at MD Anderson, in a news release. “Identifying and validating key targets in faithful model systems represents a critical first step in ultimately providing our patients with meaningful therapies.”
As a model system that was developed by DePinho during his time at the Dana-Farber Cancer Institute in Boston, the researchers used Kras-mutant mice, which developed pancreatic cancer tumors. “There’s a great deal of effort under way trying to find ways to target Kras or some of the downstream targets that it activates,” said co-lead author Haoqiang Ying, PhD, assistant professor of Molecular and Cellular Oncology. “It’s important to understand how Kras-dependent tumors might evolve in response to targeted therapy.”
After the mice developed tumors, the researchers turned off mutant Kras signaling but found the tumors recurred, independent of Kras. This indicated the tumors were able to rely on another signaling pathway through another oncogene. This oncogene was Yap1, a gene characteristic to specific pancreatic tumors that afflict patients with a poor prognosis.
“With Kras turned off, Yap1 can recreate this transcription program involving cell cycle and DNA replication machinery that is normally controlled by Kras,” said Wantong Yao, PhD, a postdoctoral fellow in Genomic Medicine. Dr. Yao conducted functional studies of the mice treated during the experiments. The genetically engineered mice had a mutant in Kras that was inducible through doxycycline administration and silenced after doxycycline was ceased.
Out of 28 mice treated, all developed tumors, and all tumors regressed within three weeks of doxycycline cessation. Within nine to 47 weeks, 20 of the mice saw recurrent tumors characteristic of aggressive cancer. Fifteen mice had cancerous tumors spread to the lung or liver. Surprisingly, some of the tumors showed no sign of Kras activity. “The only gene amplified was Yap1, which made sense, because it’s a known oncogene,” said co-lead author Avnish Kapoor, also a postdoctoral fellow in Genomic Medicine. Yap1 amplification was found by identifying copy number variations of genes within the tumors.
Yap1 is a co-activator of transcription factors and does not bind to DNA. Instead, it forms a complex with Tead2 and E2F transcription factors, allowing cell cycle activation and DNA replication to support tumor survival and growth. By knocking down Yap1 with RNA interference, the team shrank the recurrent tumors. Alternatively, by inducing Yap1 expression in the Kras mice, the team caused tumors to grow, even after doxycycline cessation.
Drugs cannot target Yap1. However, small molecule inhibitors of Yap1 have shown efficacy in stalling liver cancer progression in mice. It will be at least a few years before clinical trials can be conducted. Until then, the research team will be investigating the role of Yap1 in quasimesenchymal pancreatic cancer, which is characterized by cellular conversion through the epithelial-to-mesenchymal transition.
Pancreatic ductal adenocarcinoma affects 46,420 individuals each year, with only 6.7% of patients surviving beyond five years. It is one of the most lethal cancers, and the National Cancer Institute indicates 39,590 patients will die in 2014 from the disease. Only good news can be added by studying the signaling pathways behind cancer regression. “Characterization of these pathways may identify other potential therapeutic targets for this dreaded disease,” said Dr. Ying.