NEWS | February 1, 2016

Finding new targets to battle drug resistance


Researchers at UC Davis and Lawrence Livermore and Los Alamos national laboratories have created a chemotherapy-resistant line of bladder cancer cells to study how tumors become resistant to chemotherapy and identified molecular changes that could drive that resistance. Their research, published in the journal PLOS ONE, suggests these molecules could provide new targets to re-sensitize cancer cells to treatment.

Paul Henderson Paul Henderson

“We found a handful of novel, non-coding RNA transcripts that may be related to drug resistance,” said Paul Henderson, associate adjunct professor and member of the UC Davis Comprehensive Cancer Center. “The next step will be to knock down these transcripts to see what kinds of impact they have on the regulatory mechanisms that govern resistance. These RNAs could lead to a new understanding of drug resistance and new therapeutic approaches.”

Bladder cancer affects 70,000 people in the U.S. each year and results in 15,000 deaths. In 80 percent of the deaths, the bladder cancer had invaded the bladder wall, but there were no obvious signs of metastasis. And in half of those cases the cancer could have been cured with cisplatin-based treatment but the therapy wasn’t administered because of its toxicity and uncertainty of the response, said Ralph de Vere White, a co-author and director of the UC Davis Comprehensive Cancer Center.

“Anything that will allow us to understand why the other 60 percent of patients do not respond to this treatment could have a big impact in reducing the burden of bladder cancer,” he said.

Unlike messenger RNAs, which deliver genetic information to make proteins, non-coding RNAs have many other functions, including regulation of gene expression. Their ability to affect a cell’s genomic machinery can have a profound impact on many cellular processes.

Ralph de Vere White
Ralph de Vere White

To identify these non-coding RNAs, the UC Davis team, which also included Associate Professor Chong-xian Pan, spent ten months exposing an existing human bladder cancer cell line (called 5637) to oxaliplatin, a commonly used platinum-based chemotherapy drug.

The new cell line emerged (5637R) that was significantly less sensitive to oxaliplatin, as well as the cancer drugs carboplatin, gemcitabine and cisplatin. However, other drugs, including doxorubicin, vinblastine and methotrexate could still destroy these cells, a finding that could help guide treatment for current bladder cancer patients.

On a more granular level, the 5637R line showed many traits associated with resistant cancer cells. Higher levels of glutathione, a powerful antioxidant, increased drug resistance. 5637R cells also developed more robust DNA repair mechanisms. The next step was work to understand the genetic changes that governed these processes.

“By carefully studying these two very closely related cell lines, we could compare their genomics,” noted Henderson. “Any differences we found could potentially be related to drug resistance.”

The researchers identified 83 changes in RNA expression, many of them linked to genes already known to modulate resistance. However, the team also found 22 RNAs that had no previous association with drug resistance.

Having identified RNA molecules that may govern resistance, the researchers hope to find new compounds that can target these molecules and hopefully re-sensitize cells to oxaliplatin and other platinum-based chemotherapies.

“We have a new direction now,” said Henderson. “These findings could help us identify new, druggable targets that may one day impact therapy.”

Other researchers on the study included: Sisi Wang, Hongyong Zhang, Tiffany M. Scharadin, Maike Zimmermann, Amy Wang Pan, Ruth Vinall and Tzu-yin Lin at UC Davis; Bin Hu, Patrick Chain, Momchilo Vuyisich, Cheryl Gleasner and Kim Mcmurry at Los Alamos National Laboratory; George Cimino at Accelerated Medical Diagnostics Incorporated; and Michael Malfatti and Kenneth Turteltaub at Lawrence Livermore National Laboratory.

This research was funded by the U.S. Department of Energy (DOE) contract DE-AC52-07NA27344; NIH/NCRR Resource for Biomedical Accelerator Mass Spectrometry P41 RR013461; DOE Laboratory Directed Research and Development grant 08-LW-100; the American Cancer Society Institutional Research Grant; VA Career Development Award-2; an NCI Cancer Center Support Grant; aCancer Clinical Investigator Team Leadership Award; and NIH awards HHSN261201200048C, HHSN261201200084C, R01CA155642 and T32 CA108459-08.