Study details how resistance to targeted drug therapy emerges in colorectal cancers

A Harvard researcher studying the evolution of drug resistance in cancer is predicting that, in a few decades, "many, many cancers could be manageable."

Martin Nowak, a Harvard Professor of Mathematics and of Biology and Director of the Program for Evolutionary Dynamics, is one of several co-authors of a paper, published in Nature, that details how resistance to targeted drug therapy emerges in colorectal cancers, and suggests a new, multi-drug approach to treatment could make many cancers manageable, if not curable, illnesses.

The key, Nowak's research suggests, is to change the way clinicians battle the disease.

Though physicians and researchers in recent years have increasingly turned to "targeted therapies" - new drugs which combat cancer by interrupting its ability to grow and spread - rather than traditional chemotherapy, the treatment is far from perfect. Most are only effective for a few months before the cancer evolves resistance to the drugs and is able to grow unchecked.

In the particular colon cancer treatment that was the subject of Nowak's research, the culprit is the KRAS gene. Normally responsible for producing a protein to regulate cell division, when activated, the gene helps cancer cells develop resistance to targeted therapy drugs, effectively making the treatment useless.

Based on analysis completed by Benjamin Allen, a Post-Doctoral Fellow in Mathematical Biology, and Ivana Bozic, a Post-Doctoral Fellow in Mathematics, Nowak's research suggests that, of the billions of cancer cells that exist in a patient, only a tiny percentage - about one in a million - are resistant to drugs used in targeted therapy. When treatment starts, the non-resistant cells are wiped out. The few resistant cells, however, quickly repopulate the cancer, causing the treatment to fail.

The answer, Nowak argued, is simple - rather than the one drug used in targeted therapy, treatments must involve at least two drugs.

Nowak isn't new to such suggestions - in 1995, he participated in a study, also published in Nature, that focused on the rapid evolution of drug resistance in HIV. The end result of that study, he said, was the development of the drug "cocktail" many HIV-positive patients use to help manage the disease.

Ultimately, Nowak estimated that hundreds of drugs might be needed to address all the possible treatment variations. The challenge in the near term, he said, is to develop those drugs. Once available, though, he believes the multi-drug approach offers a new avenue for cancer treatment, one that may fundamentally alter how the public views the disease.

"This will be the main avenue for research into cancer treatment, I think, for the next decade and beyond," Nowak said. "As more and more drugs are developed for targeted therapy, I think we will see a revolution in the treatment of cancer."