Solving the Treatment Resistance Riddle

Celeste Mills lived with metastatic breast cancer for 14 years before her unexpected death in August. Between 1999 and 2013, she underwent a succession of treatments involving various chemotherapy agents, targeted drugs and combinations. “Whenever we started to lose some ground, my doctor added different medicines,” Mills said. “One would kick it back for awhile, then it would stop working, and we’d try something else.”

Mills, who lived outside Los Angeles, said she wasn’t surprised that dealing with her cancer turned into such a complicated affair. “These cancer cells have been living here a long time,” she said. “They know my body better than I do.”

In many ways, she was right, says Michael Gottesman, head of the multidrug resistance section at the National Cancer Institute in Bethesda, Md. “The cell will do anything it can to survive,” Gottesman says. “Biology is trying to outwit us.”

Cancer cells can resist chemotherapies and other treatments through a variety of mechanisms that can sometimes seem bewildering. Treatments can’t get to where they’re supposed to go because cancer cells can stick together, protecting those on the inside. Tumor cells pump out the toxins that were supposed to get inside to kill them. It’s not that cancer cells are smart, it’s just that genetic variability within a single tumor can allow a fraction of its cells to resist treatment and proliferate. Tiny genetic alterations can transform a cancer cell’s vulnerability to a drug.

Despite cancer’s “ingenuity,” Gottesman says, research is deciphering how to circumvent or tackle resistance. “I tell patients this is not a single battle, it’s the beginning of a war, and we have an armamentarium of weapons,” he adds. “First, we’ll try the ones that are the most likely to work. Then we have a second set. And another.

“And we’re also getting more intelligent,” Gottesman says, describing the role of research. “Our spies are learning more about the enemy so that we can develop more weapons.”

We’re also getting more intelligent. Our spies are learning more about the enemy so that we can develop more weapons.

He and other experts in the field of cancer resistance say they’re buoyed by what they’re learning, not frustrated, because better understanding will lead to better treatments. Samuel Aparicio, a researcher in molecular oncology at the University of British Columbia and the BC Cancer Agency in Vancouver, British Columbia, says he sees an analogy with AIDS, which is caused by a virus that— like cancer—uses evolutionary tricks to evade cure.

“AIDS has become a more chronic than deadly disease, treated with antiretroviral therapies,” Aparicio says. “The breakthrough there was that people realized you had to combine three different treatments to stop the virus from evolving.” The breakthrough in beating cancer’s evasiveness is likely to be different in detail, but not in outcome. Aparicio and others envision a future in which advanced cancer is a chronic disease, not invariably a deadly one.

To understand how cancer cells acquire the ability to elude therapy in so many ways, “back up and consider that we all evolved in a background of very toxic materials,” Gottesman says. The first cells to evolve on Earth had to survive in a very hostile environment, he explains, “so some of the very first genes that evolved, their function was to create a privileged environment inside a cell that would allow life to go on.”

Today, he and other researchers define two general categories of resistance: intrinsic and extrinsic.

Intrinsically, many tumor cells already contain tools and tricks allowing them to resist chemotherapy or other treatment, even the first time it’s applied.

“Consider the liver, which is in charge of detoxifying all this garbage in our bodies,” Gottesman says. “It has all these pumps and enzymes active in it to remove toxic materials.” Thus, if cancer develops in liver cells, those cells are more likely to resist therapies from the start.

Gottesman and his colleagues study the tiny, cellular “pumps” in tumor cells responsible for multidrug resistance, which lets cells remove almost any chemotherapy oncologists are trying to get inside the cell to kill it.

“And if it does get inside, the cell is just full of ways to detoxify chemicals,” Gottesman says. “They can conjugate, sequester… that’s intrinsic resistance.”

Cancer cells can also develop such resistance because of extrinsic pressures, including the pressure of chemotherapy itself, which is geared to selectively kill sensitive cells.

On the other hand, blood and bone marrow are not ordinarily exposed to highly toxic compounds, so leukemia tumor cells might not generally have some natural detoxifying pathways “turned on” or expressed. Send in chemotherapy and most of those cells will die.

But cancers are not made up of identical cells. A few stray cancer cells can randomly express genes that activate “pumps” to remove toxic chemicals or other genes using different mechanisms to protect the cell from deadly agents. Those cells are the ones most likely to survive cancer treatment, and those cells can then grow and proliferate.

Cancers can also establish new ways to grow when chemotherapies or other treatments initially block the tumor. Antonio Jimeno, an associate professor, researcher and oncologist at the University of Colorado Cancer Center in Denver, says this mechanism is a powerful one in certain types of resistant leukemias and lung cancers.

Cancers are not made up of identical cells. A few stray cancer cells can randomly express genes that activate “pumps” to remove toxic chemicals or other genes using different mechanisms to protect the cell from deadly agents. Those cells are the ones most likely to survive cancer treatment, and those cells can then grow and proliferate.

Patients whose cancers contain a mutation in a gene called epidermal growth factor receptor (EGFR), for example, might do remarkably well on treatment for awhile, he says, “but eventually, the tumor finds cells that lack the mutation or are not susceptible, and those cells take off,” or proliferate. For example, researchers examined the genetic makeup of metastatic non-small cell lung cancer in one patient who developed resistance to a targeted therapy. The metastases all contained a mutation that wasn’t present at the start of treatment, and that interfered with the drug’s ability to bind to its target.

“I look at this as similar to an electrical switch or plan in a house,” Jimeno says. “We turn off one switch, and sometimes the tumor can turn it back on, or find alternative wiring.”

Jimeno’s research team is studying yet another mechanism of resistance—something he calls “the plasticity of tumor-initiating cells,” or the ability of some cells to take on the characteristics of other cells.

I look at this as similar to an electrical switch or plan in a house. We turn off one switch, and sometimes the tumor can turn it back on, or find alternative wiring.

Tumors are complex, made up of many cells that divide and proliferate quickly, as well as some more slowly dividing cells called tumor-initiating cells, also termed cancer stem cells, that can re-grow the tumor. Because chemotherapies tend to target rapidly dividing cells, one theory suggests tumor-initiating cells are better able to weather the storm of chemotherapy.

“The tumor may shrink initially, but as the proportion of tumor-initiating cells increases, it can become active again,” Jimeno says. “So, what we are doing is trying to understand what makes those cells different from the more rapidly dividing cells and what allows them to avoid treatment-induced death.” Jimeno is a principal investigator on an active trial involving an antibody drug, called OMP-54F28, which targets a growth pathway in tumor-initiating cells.

Mills and her oncologist struggled with the development of extrinsic resistance in her cancer. She received her initial breast cancer diagnosis in 1991, when she was still in her 30s, but the disease was caught early and treated aggressively. “I went eight years without any evidence of cancer,” Mills said.

Then, in 1999, she began to experience chest pain. It was soon clear that her breast cancer had metastasized to her bones. Her tumor cells overexpressed a receptor called HER2, and HER2-positive cancers tend to be aggressive. They can, however, be treated with the antibody-based drug Herceptin (trastuzumab), which targets cells that overexpress the HER2 receptor, blocks those receptors and slows or stops cancer growth.

“I did quite well on that drug for more than a decade,” Mills said. “And then, a couple years ago, we started to lose ground a bit.” Tumors in her bones stopped responding to the treatment.

That’s not unusual. For Herceptin-resistant tumors, there’s evidence that several processes can lead to resistance. HER2 receptor pathway components can mutate so that Herceptin no longer blocks the growth signal. Tumor cells can also activate different receptors to bypass the HER2 receptors, and the cells can grow rapidly again.

Mills began taking Kadcyla (ado-trastuzumab emtansine, or T-DM1) soon after the Food and Drug Administration approved it in February. With both an antibody (Herceptin) and a cell-killing agent (emtansine), Kadcyla seeks out HER2-positive cancer cells specifically, and then delivers its toxin. That drug worked well for several months, Mills said.

Mills acknowledged it wasn’t always helpful to know the details of how her cancer developed resistance or exactly why a shift in drugs—again—might slow the growth of bone metastases. But, she added, it was powerfully important for her to know that her advanced cancer could develop resistance and that shifting treatments regularly was not unusual.

“Patients can start to feel that they’re the only ones going through it,” Mills said, “or that somehow it’s their fault. It’s not a matter of whether you’re worthy; it’s a matter of body chemistry,” she added.

Andy Bonnett of Denver has also fought resistant cancer. He received a diagnosis of non-small cell lung cancer in 2008 at age 34 and endured 10 difficult months of chemotherapy.

“They hit me pretty hard with it because I was young,” Bonnett says. For several months, a cocktail of chemotherapy agents kept his tumors, scattered through his lungs, at bay. But then the tumors began to grow again.

“I couldn’t do it anymore,” Bonnett says. He discontinued chemotherapy and traveled internationally to try alternative approaches to fighting his disease. He then received an email from his girlfriend in Denver, whose friend had seen a news item about a promising clinical trial at the University of Colorado. Within a month, Bonnett had enrolled. The trial was for Xalkori (crizotinib), a targeted drug that blocks a key protein involved in cancer cell growth and proliferation. The target: cancers with a mutation in the anaplastic lymphoma kinase (ALK) gene—the type of mutation found in the cancer that Bonnett had.

Today, he chokes up when he remembers looking at the first scan after beginning the trial in 2009. “It was amazing,” Bonnett says. “In my baseline scan, the biggest tumor was marked with this huge X. In the next scan, you couldn’t see it anymore.”

In painstaking detail, researchers are trying to understand— and outwit—the genetic and other cellular processes that lead cancer cells to resist, or evolve to resist, treatment. Their findings are leading to clinical trials with novel and combination approaches to cancer treatment, and the efforts bode well for the future.

Last year, researchers reported that non-cancerous cells (fibroblasts) near metastases could be stimulated by chemotherapy to unintentionally protect their cancerous neighbors. Fibroblasts exposed to drugs that damage DNA (such as many chemotherapy agents) produced a protein called WNT16B, which helped neighboring cancer cells not only resist chemotherapy but grow and invade surrounding tissues. Researchers see the processes involved as targets for new therapies.

Other anticancer therapies in development trigger cancer cells to commit suicide (apoptosis), but cancers— especially those with cellular changes—can be quick to develop resistance to apoptosis. Researchers hope that understanding the detailed reactions inside cells exposed to the agent will lead to technologies that enable them to overcome the resistance.

And researchers know a great deal more about the mechanisms of multidrug resistance than they did a decade ago. Although some experimental drugs to overcome this have proven too toxic, others are being investigated. Moreover, cancers that resist almost all treatments often overexpress one of two key membrane proteins, which actively pump out toxins that might otherwise kill the cell. Researchers are trying to circumvent this type of resistance by delivering toxic drugs into a different part of the cell—the mitochondria—which might limit the drug removal process.

Surveillance tools, such as near-realtime sequencing of tumor cells’ genetic makeup, promise to give clinicians immediate information on tumor genetics as well as changes following cancer treatment. Such tools could enable doctors to switch treatment approaches when warranted and reduce use of therapies almost certain to be ineffective.

Aparicio says these and many other innovations give him hope. “In 10 years, we’ll know a lot more about what makes cells resistant, and when we evaluate patients for therapy, we’ll be—from the get-go—looking at combinations of treatments to help suppress all mechanisms of resistance, not just some.”

Bonnett has had to deal with further shifts in his cancer makeup and treatment. Last summer, his tumors began showing signs of resistance to Xalkori. He started to feel a return of the pain that marked his original disease. After returning from a kayaking trip for people with cancer, Bonnett underwent new scans, which revealed multiple lesions.

He was eligible, however, for a second clinical trial, one with a new agent, still unnamed, called AP26113, which also targets ALK in a different way. AP26113 seems to be able to make it through the blood-brain barrier, and today, Bonnett’s brain metastases are inactive.

Mills was doing well, too, until August, when she unexpectedly died from pneumonia. At the time, there was no evidence that her cancer had progressed, and her sister, Susan Breen, says she was even feeling well enough to have planned a late summer vacation. Then, Mills took “a nasty fall,” Breen says.

A baby bird had fallen from its nest in a hanging plant on Mills’ patio, Breen explains. “She got a stepstool from the kitchen and moved it outside to get the baby bird back home.” She fell from the stool and landed hard on the edge of the concrete patio, shattering her leg. Breen believes the fall would have hobbled a healthy person, much less her sister, whose long-term metastatic cancer and treatment had left her with fragile bones.

Mills’ recovery from the fall was difficult, and fear of falling again made her more sedentary, which contributed to the pneumonia, Breen adds.

“It was so uncharacteristic of her to be afraid,” Breen says. “She had the courage to do anything, regardless of how unconventional and despite what others thought.” Breen says. Her sister had been a magician, a hypnotherapist, a breeder of prize-winning golden retrievers, and had often ignored raised eyebrows while pursuing her passions.

“That indomitable spirit lasted her entire life,” Breen says. “Her strength and wonderful sense of humor never flagged.”

About a week before her death, Mills said in an email that she was looking forward to sharing her story with CURE. “I consider myself incredibly fortunate,” she wrote. “I’ve had more than 20 years since first diagnosis.”

Editor’s Note: Celeste Mills died on Aug. 26. CURE is proud to honor her memory.