Study Seeks Novel Pathways for Chemo Sensitivity, Resistance

Her findings may help determine whether a particular cancer-fighting drug will be successful in individual patients, eliminating the need for trial-and-error approaches to treatment.

Surtees and her team are using the budding yeast Saccharomyces cerevisiae as a model system. They expect to uncover novel genetic pathways affected by altered levels of deoxyribonucleotide triphosphates (dNTPs) — substrates critical for DNA replication and repair — by taking advantage of yeast strains with altered dNTP pools.

The researchers will perform high-throughput genomic screens with these strains, analyzing more than 4,700 mutants representing every non-essential gene in yeast. 

“This will allow us to identify pathways that allow cells to grow better or worse in the presence of altered dNTP pools,” Surtees notes.

The researchers also will test the mutants for their ability to survive in the presence of different DNA-damaging agents, including chemotherapeutics. Mutations that increase sensitivity to these drugs could indicate pathways that might also sensitize cancer cells.

The findings could lead to improved cancer treatment by identifying new candidates for targeting fast-growing cancer cells, says Surtees.

“By developing a better understanding of how elevated dNTP pools affect the cell, we can potentially target pathways to make these cells more susceptible to treatments, ultimately resulting in combination treatments that enhance chemotherapy.”

In addition, the research on mutants could provide insight into mechanisms that make cancer cells resistant to DNA-damaging drugs.

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 a 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.

The focus on dNTPs also will shed light on a potentially carcinogenic process, illuminating how cancer may develop.

In the right amount, dNTPs are needed to repair DNA damage, Surtees explains.

“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,” she says. “Without a sufficient level, 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, leading to genetic diseases, including cancer.”

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

Surtees has received a $792,000 Research Scholar Grant from the American Cancer Society for the basic science study.