UT Southwestern Medical Center researchers have discovered a new approach to treating a common type of chemo-resistant lung cancer. The study identified a 35-gene signature in tumor cells that are most likely to develop resistance to chemotherapy treatment.
Non-small-cell lung cancer accounts for 85 percent of all lung cancer cases in the United States, as estimated by the American Cancer Society. Patients with these cells often respond to standard chemotherapy, only to later develop resistance to treatment and experience potentially a fatal relapse.
Resistance to chemotherapy is a “big cause” of cancer treatment failure, said study co-author Dr. John Minna, a professor and director of UT Southwestern’s Hamon Center for Therapeutic Oncology Research. But the study’s findings could point to a way to prevent resistance in the first place.
Researchers studied mouse and cellular models of NSCLC to identify genes commonly altered during the development of resistance. Their discovery was a 35-gene signature that indicated a greater likelihood of chemotherapy resistance.
Dr. Elisabeth Martinez, study senior author and assistant professor of pharmacology at UT Southwestern, said in a news release that the genetic signature is “like a fingerprint for resistance.” Researchers then compared the genetic signature to genetic profiles of human tumors. The 35-gene signature positively correlated with the genetic profiles of NSCLC patients in the database who experienced relapse.
Researchers also found that as cancer cells develop resistance, the cells produce a greater amount of enzymes. Cells use these enzymes to change gene expression and survive the toxic stress of chemotherapy. “By changing the expression of genes, the tumor cells can adapt and survive the toxins,” Martinez said.
But the more chemo-resistant a cancer cell is, the more dependent the cell is on the enzymes for survival. This means that inhibiting enzymes leaves the cancer cells more vulnerable to cell death.
Dr. Maithili Dalvi, lead author of the study and a former postdoctoral researcher, said that the inhibitors “appear to be much more potent in killing cancer cells than normal cells” in their experiments.
Two inhibitors have succeeded in cellular models and partially prevented resistance in animal models. These inhibitors have the potential to be used either to treat resistant tumors or to prevent resistance altogether, Dalvi said: “The cancer cells develop a new Achilles’ heel that we can hit.”
Martinez said she and the other researchers plan to continue testing in mouse and human models. “We will likely also evaluate our strategy in other cancer models to see how general it is,” Martinez said in an email, “and to establish if the mechanisms we uncover also apply to the development of resistance to other types of chemotherapy.”