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Mutant Kras drives pancreatic cancer maintenance via metabolic pathways
Date:4/26/2012

as) and bred it into mice. This allowed the scientists to initiate expression of Kras in the pancreas by treating the mice with doxycycline and turn it off by withdrawing the drug.

Ying was a postdoctoral fellow in DePinho's lab at Dana-Farber before moving to MD Anderson after DePinho became president last September.

"These studies not only established that oncogenic Kras serves a tumor maintenance role, they allowed us to explore exactly how this occurs by extinguishing Kras in fully formed tumors," DePinho said.

Kras extinction causes tumor regression, deterioration

Pancreatic cancer progression is accompanied by the inactivation of a variety of tumor-suppressing genes. The team crossed its inducible Kras mice with others that had the tumor-suppressor p53 knocked out. Mice with either only iKras or iKras and deficient p53 were treated with doxycycline at three weeks of age.

  • All iKras mice with p53 deficiency died of pancreatic cancer between 11 and 25 weeks of age with median survival of 15 weeks.
  • The iKras/p53 mutant tumors had features commonly found in human pancreatic cancer, such as glandular tumor structures, invasion of local organs and metastases to the lung and liver.

Withdrawing doxycycline renders the iKras transgene extinct within 24 hours. Mice with iKras without p53 developed invasive pancreatic cancer by week eight after treatment.

When the researchers withdrew doxycycline at week nine:

  • Tumors swiftly regressed in size and visibly deteriorated after 48 hours.
  • After a week, MRI showed a reduction in tumor mass of about 50 percent, and PET/CT scans showed cessation of glucose uptake by the tumors.
  • Programmed cell death increased, tumor cell proliferation dropped and supportive tissue in the tumor - stroma - also was altered.
  • Signaling by downstream components of the Kras pathway, such as MAPK and mTOR, dropped.

Kras
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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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