Tumor Cells Become Drug Resistant by Reverting to a Stem Cell-Like State, New Study Finds

It’s every cancer patient’s fear: that the drugs being used to shrink their deadly tumor stop working.

Faced with this stark reality, researchers have become trapped in a molecular ‘arms race,’ trying to develop more effective therapies to attack the cancer. A better solution would be to prevent the drug resistance at the outset, but thus far scientists have struggled to understand the underlying mechanism of resistance.

Now, scientists at the University of California, San Diego School of Medicine have discovered a molecule on the surface of tumors that appears to promote resistance—by converting the tumor cells back into a stem cell-like state. The results, published in Sunday’s issue of the journal Nature Cell Biology, point to a new way to cut off drug-resistant tumors at the source.

Drug-resistant cancer is a persistent problem that has plagued the oncology community and doctors are desperate for a new solution. As the study’s lead author and David Cheresh points out in a recent news release,

“There are a number of drugs that patients respond to during their initial cancer treatment, but relapse occurs when cancer cells become drug-resistant. We looked at the cells before and after they became resistant and asked, ‘what has changed in the cells?’”

In order to answer that question, the research team focused their efforts on two commonly used cancer drugs, erlotinib and lapatinib, monitoring the physical and chemical properties of individual tumor cells as they were treated with the drugs over time. And what they found taking place was a very peculiar transformation.

When the tumor cells began to exhibit drug resistance, the cells were simultaneously transforming into a stem cell-like state, which made them impervious to the drugs. In effect, they were able to hide from the drugs in plain sight. Importantly, these findings shed new light on cancer stem cells, the existence of which has long been a subject of debate among the medical community. This study could generate a chicken-and-egg debate about what comes first, cancer stem cells or the original tumor, or do stem cell-like cancer cells exist at two points in time.

Most troublingly, explained Cheresh, was that it appeared that the treatment itself was driving this transformation by activating a specific molecular pathway.

Luckily, the team also identified several existing drugs that attack this pathway and reverse the cellular transformation, thus ‘re-sensitizing’ the tumor. And within the next year, Hatim Husain at the Moores Cancer Center in La Jolla, CA will begin a clinical trial testing the effectiveness of this strategy in patients with drug-resistant lung cancer. As Husain explained in the same news release:

“Based on these research findings we now better understand how to exploit the ‘Achilles Heel’ of these drug-resistant tumors.”

Husain and his colleagues are optimistic that combination therapies that keep the disease under control, but also combat drug resistance, are our best bet for reducing mortality and improving quality of life.

Eventually, he hopes that treatments can evolve to such a level that they can prevent drug resistance before it even begins. This is welcome news for the millions of patients and their families who must constantly wage new battles each time their cancer becomes drug resistant.

To find out how CIRM-funded scientists are harnessing the power of stem cells to fight cancer, check out our disease programs in leukemia, brain cancer and melanoma.

Photo caption: In the above image, drug-resistant tumor cells are shown in brown [Credit: UC San Diego School of Medicine]

Anne Holden

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