University of California San Francisco
Helen Diller Family Comprehensive Cancer Center

Genetic 'Balance' May Influence Response to Cancer Treatment

UCSF-Led Team Finds That Both Normal and Mutant Gene Copies Are Key

By Pete Farley | | February 27, 2017

Genetic 'Balance' May Influence Response to Cancer Treatment

KRAS Protein Structure. Image courtesy the National Cancer Institute.

Choosing among cancer treatments increasingly involves determining whether tumor cells harbor specific, mutated “oncogenes” that drive abnormal growth and that may also be especially vulnerable or resistant to particular drugs. But according to a new study led by UCSF researchers, in the case of the most commonly mutated cancer-driving oncogene, called KRAS (pronounced “kay-rass”), response to treatment can change as tumors evolve, either when a normal copy of the gene from the other member of the matched chromosome pair is lost, or when the cancer cells evolve to produce additional copies of the mutated form of the gene.

The identification of distinctive abnormalities in DNA sequences within the genomes of tumor cells from biopsy specimens is becoming a more common aid to help guide cancer treatment decisions, and the authors of the new study, published in the February 23 edition of Cell, said their discovery of KRAS “imbalances” that emerge over time could be added to a growing list of genetic characteristics that may be clinically valuable.

Kevin Shannon

Kevin M. Shannon, MD

“It’s an unexpected result and a new idea for the field of cancer genetics,” said the study’s principal investigator, Kevin Shannon, MD, the Roma and Marvin Auerback Distinguished Professor in Pediatric Molecular Oncology at UCSF. “Those who enter the field are taught that oncogenes represent a dominant-acting mutation that is able to help drive abnormal growth within the tumor, and that a normal copy that is not mutated doesn’t matter much. These new data show that the status of the normal copy of the gene can in fact matter in some cancers when it comes to determining whether tumor cells are sensitive to drug treatment.”

Working with mice to generate multiple different leukemias that had a variety of easily traced genetic abnormalities and that could be easily transplanted and treated in additional mice, the scientists identified an especially interesting “outlier” — a cancer that was exceptional for its robust growth before treatment, for the duration of its responsiveness to a specific type of targeted therapy called a MEK inhibitor, and for the way that it became resistant to that drug over time. These factors allowed the researchers to home in on the association between specific genetic changes and differences in treatment response.

This leukemia had a mutated KRAS gene on each chromosome, which enabled the cancer to grow aggressively, but also made it vulnerable to treatment with the MEK inhibitor. After treatment, the leukemia relapsed, and a third chromosome had emerged that carried a normal copy of KRAS, rendering the disease resistant to the drug.