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A new class of drugs could be effective for more tumor types than previously assumed. An international team, in which researchers from the Freiburg University Medical Center played a key role, has shown that so-called SHP2 inhibitors could also be effective against tumors that were previously difficult to treat, such as pancreatic cancer and certain types of lung cancer. They also discovered how tumors become resistant to drugs and how this resistance can be reversed. The researchers therefore recommend that patients with these types of cancer be included in ongoing studies with SHP2 inhibitors. The study was published on May 28, 2018 in the journal Nature Medicine.

Lung and pancreatic cancers are also known as KRAS tumors, as they are often caused by the same genetic defect. This mutation leads to the KRAS protein, which is responsible for cell division among other things, being permanently active. The cell divides uncontrollably and tumors develop. Every third tumor in humans is considered a KRAS tumor. The problem is that the KRAS protein is also active in healthy cells and is so important that it cannot simply be switched off therapeutically.

"Until now, it was assumed that the KRAS mutation makes the tumor so aggressive that therapeutic attacks at other sites have no effect," says the first author of the study, Dr. Dietrich Ruess, a physician at the Department of General and Visceral Surgery at the Freiburg University Medical Centre (Medical Director: Prof. Dr. Stefan Fichtner-Feigl).

New weapon against KRAS-mutated tumors

In the current study, the team led by Dr. Ruess and principal investigator Prof. Dr. Hana Algül from the Technical University of Munich disproved the previous assumptions of experts. They showed that inhibitors of the SHP2 class also stop KRAS tumors. So far, they have only been tested for growth factor receptor-dependent cancers. "To our surprise, the new drug class is also effective against aggressive KRAS tumors. This makes them promising drugs," says Dr. Ruess confidently.

SHP2 protein is essential for tumor growth
 

Among other things, Dr. Ruess and his colleagues worked with mice that produce a defective KRAS protein in pancreatic or lung cells. These animals very frequently developed tumors. When the scientists removed the SHP2 protein from the animals, they no longer formed tumors. The team was thus able to prove that SHP2 is essential for tumor formation and could be a new target for therapies for particularly aggressive tumors with KRAS mutations.

The results were confirmed when the researchers removed the SHP2 protein from tumors or used SHP2 inhibitors in the animals. "The existing tumors grew more slowly when the SHP2 inhibitor was used and could be better controlled," explains Dr. Ruess.

Combination of active ingredients helps against resistance

The new study could also provide a solution to another problem in the treatment of KRAS tumors: They often become resistant to drugs. The scientists were able to understand how this resistance to certain anti-cancer drugs develops. It turned out that SHP2 also plays a central role in this process. By inhibiting SHP2, the resistant cancer cells become accessible to the old drug again. "A combination of both active substances could therefore be a new therapeutic option for resistant tumors," says Prof. Algül.

"In future, the new inhibitors could help both on their own and in combination with existing drugs. For many patients with aggressive tumors, this could be life-prolonging," says Dr. Ruess. The researchers therefore recommend including patients with pancreatic or lung cancer in the ongoing studies on SHP2.

Original title of the publication: Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase

DOI: 10.1038/s41591-018-0024-8

Link to the study: https: //www.nature.com/articles/s41591-018-0024-8

Contact: 
Dr. Dietrich Ruess 
Department of General and Visceral Surgery 
University Medical Center Freiburg 
Phone: 0761 270-24010 
dietrich.ruess@uniklinik-freiburg.de