Novel cellular mechanism for pancreatic cancer drug resistance identified

Pancreatic cancers dependent on signaling from a mutant Kras gene for their growth and progression in the laboratory are able to switch to Yap1, another oncogene, if Kras is blocked.

Kras is a gene for a cell membrane protein that plays a critical role in normal tissue signaling, and mutation of the Kras gene is an essential step in the development of many cancers.

When researchers increased levels of mutant Kras to spur pancreatic cancer growth in mice then turned the gene off, some tumors were able to grow back by relying on Yap1, a different oncogene. In addition to discovering a resistance mechanism for Kras-dependent tumors, the team found that tumors dependent on Yap1 resemble a type of pancreatic tumor with a poor prognosis.

"There's a great deal of effort to find ways to target Kras or some things it activates," said author Haoqiang Ying, PhD, assistant professor at The University of Texas MD Anderson Cancer Center, Houston, Texas. "It's important to understand how Kras-dependent tumors might evolve in response to targeted therapy."

Pancreatic ductal adenocarcinoma is one of the most lethal of cancers, with only 6.7 percent of patients surviving for 5 years. An estimated 46,420 new cases will be diagnosed in 2014, and approximately 39,590 people will die of the disease, according to the National Cancer Institute.

"Pancreatic cancer remains an intractable disease with limited therapeutic options," said senior author Ron DePinho, MD, president of The University of Texas MD Anderson Cancer Center. "Identifying and validating key targets in model systems represents a critical first step in providing patients with new therapies."

Mutations that activate the Kras gene are present in most human pancreatic cancers. Experiments with genetically engineered mice have demonstrated that these mutations play critical roles in tumor initiation and progression.

The mice have a version of the Kras gene that can be activated by treatment with the antibiotic doxycycline, leading to the development of pancreatic cancer. Tumors develop swiftly but begin to regress within 24 hours of cessation of doxycycline treatment.

All 28 mice had complete tumor regression within 3 weeks of doxycycline cessation. Then, 20 of the mice had tumor recurrence 9 to 47 weeks later. The recurrent tumors had characteristics of aggressive disease, including spread to the lung or liver in 15 mice.

Half of the recurrent tumors had re-expressed the inducible Kras transgene, while the other half had no sign of the oncogene or activation of its related molecular pathways.

Analysis of variations in the copy number of genes in the tumors showed that Yap1, a known oncogene, was responsible for the tumor recurrence. Yap1-amplified recurrent tumors shrank when Yap1 expression was reduced via RNA interference.

Yap1 is involved in cell proliferation, a cellular conversion known as epithelial-to-mesenchymal transition, cancer invasion, and metastasis. Amplified copies of the Yap1 gene have been found in liver, oral squamous cell, and esophageal cancers as well as in medulloblastoma.

Yap1 drives tumor recurrence and progression; however, evidence shows that it is insufficient to cause initial formation of pancreatic cancer.

Although Yap1 and Kras cannot be targeted directly with drugs at this time, small molecules targeting Yap1 have stalled liver cancer progression in a mouse model.

This study was published in Cell (2014; doi:10.1016/j.cell.2014.06.003).

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