Ramped up DNA repair pathways in cisplatin-treated cells are the cause, according to study in Genes and Development.

MIT cancer biologists report that they have found how resistance to cisplatin arises. Tumor cells treated with cisplatin enhance their DNA repair pathways, allowing them to evade cell death, says lead author, Trudy Oliver, Ph.D., a postdoctoral fellow in the lab of Tyler Jacks, Ph.D.

Dr. Jacks, director of the David H. Koch Institute for Integrative Cancer Research at MIT, led the research. Results will be published in the April 15 issue of Genes and Development. The paper is called “Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer.”

Cisplatin and other platinum-based cancer drugs destroy tumor cells by binding to DNA strands, thus interfering with DNA replication. That activates the cell’s DNA repair mechanisms, but if the damage is too extensive to be repaired, the cell undergoes programmed suicide.

Previous studies had suggested several possible mechanisms for resistance development, including enhancement of DNA repair pathways, detoxification of the drug, and changes in how the drug is imported into or exported out of the cell.

Those studies were, however, done in cancer cells grown in the lab, the MIT group points out. “Many mechanisms have been identified, but it’s not clear what happens in vivo because the in vivo environment is so much more complicated than in cell lines,” Dr. Oliver points out.

She and her team thus set out to study cisplatin resistance in mice with a mutation in a gene called Kras, which leads the animals to develop lung cancer. Some of the mice also had defective versions of the tumor suppressor gene p53.

The researchers found that cisplatin was effective against lung tumors in both sets of mice, though it was more potent in mice that still had functional p53. In those mice, tumors actually shrank, while the drug only slowed tumor growth in mice with defective p53. These results are consistent with findings in human patients, the scientists note.

After four doses of cisplatin, mice with normal p53 developed resistance to the drug, and tumors started growing faster. To figure out why, the researchers analyzed which genes were being transcribed more as resistance developed.

They identified several that are involved in DNA repair pathways. The scientists say that one gene particularly caught their attention: PIDD (p53-induced protein with a death domain), which is turned on by p53 and has been implicated in programmed cell death, though its exact function is not known. When PIDD levels are artificially increased in human lung cancer cells, they become more resistant to cisplatin.

Dr. Oliver is now studying tumors in which the PIDD gene has been knocked out, to see if its absence hinders drug resistance. It is likely that PIDD is just one of many genes, in many pathways, involved in the drug resistance process, says Dr. Oliver. “It’s not a simple phenomenon.”

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