Making cancer cells more sensitive is goal of UB study

BUFFALO, N.Y. – What makes cancer cells sensitive or resistant to chemotherapy?

University at Buffalo researchers are working on an answer, thanks to a $792,000 grant from the American Cancer Society.

The research will eventually help determine, prior to treatment, whether or not a particular chemotherapy will be successful in an individual patient, a significant improvement from the trial-and-error methods to which many patients are still subjected.

Jennifer Surtees, PhD, associate professor in the UB Department of Biochemistry and principal investigator, is studying the genetic pathways that make cancer cells susceptible or resistant to chemotherapies. Her research focuses on pathways affected by changes in levels of substrates that are critical for DNA replication and repair, called deoxyribonucleotide triphosphates (dNTPs).

“When your cells are about to either divide or repair DNA damage, dNTPs are necessary to build, or write, the new copy of your genome,” Surtees explains. “Without a sufficient level of dNTPs, DNA synthesis will stall.  But when levels of dNTP pools are too high, the proteins that copy our DNA tend to make more mistakes so mutations increase. It’s as if the cell’s normal ‘spell-checker’ function gets overwhelmed, leading to genetic diseases, including cancer.”

Many cancer cells have elevated dNTP pools, explains Surtees. “That’s what supports their rapid proliferation,” she says.

Surtees and her colleagues are using the budding yeast Saccharomyces cerevisiae as a model system to identify genetic pathways that are affected by altered dNTP levels.  To do this, they will analyze the growth characteristics of more than 4700 mutants, representing every non-essential gene in yeast.  These same mutants will then be tested for their ability to survive in the presence of different DNA damaging agents, including chemotherapeutics that are known to damage DNA.   Mutations that increase sensitivity to these drugs could indicate pathways that might also sensitize cancer cells.

“We expect to uncover novel pathways that impact cellular growth under conditions where dNTP pools are elevated,” says Surtees. “This will provide new candidates for targeting fast-growing cancer cells. By developing a better understanding of how elevated dNTP pools affect the cell, we can potentially target pathways to make the cancer cells (with elevated dNTPs) more susceptible to cancer treatments, ultimately resulting in combination treatments to enhance chemotherapy.”

In addition, mutants that increase resistance to different DNA damaging drugs could provide insight into the mechanisms that lead to drug resistance in cancer cells.  Currently, Surtees says, scientists do not have a good understanding of the pathways leading to resistance to chemotherapeutics, although genetic background is a factor.

“Through the combination of genomic and chemical approaches, we hope to identify pathways that will help us understand how cells become resistant to different chemotherapeutic drugs,” she says.