Turning Resistance Into Opportunity

WHEN ROBERT GATENBY FIRST became a radiologist in the early 1980s, he couldn’t have imagined the range of effective cancer treatments now available. He also couldn’t have predicted the number of ways that cancer cells, through acquired mechanisms and mutations, can evade those treatments and continue to grow.

“When I first came out of training, people died [from cancer] because there weren’t good therapies; there just really wasn’t much,” says Gatenby, a clinical radiologist at Moffitt Cancer Center in Tampa, Florida. But researchers’ efforts to develop new treatments have improved outcomes for patients, he says. Based on the most recent data, an estimated 70% of people who are diagnosed with cancer in the U.S. are living for five years or longer. In addition, treatments have extended survival for people with once-categorically fatal cancers, such as multiple myeloma, melanoma, and liver and lung cancers.

But some realities remain the same. While many advanced cancers respond to treatments for long stretches of time, people with metastatic disease often find that these treatments stop working, requiring them to switch to a different option. In fact, approximately nine out of every 10 cancer-related deaths are attributed to treatment resistance.

“Drug development efforts have brought a large number of new agents and new strategies so that there’s pretty good therapy for nearly all primary cancers, and yet metastatic cancer remains a fatal disease,” says Gatenby. He adds, in almost all cases, the proximate cause of death is cancer evolution.

Why Does Treatment Resistance Develop?

In evolution, genetic differences arise within a population, leading to variations in traits that can be passed on from one generation to the next. Those genes and features that confer an advantage tend to get passed on to future generations. This evolution translates to basic survival of the fittest.

Cancer cells also evolve, first by acquiring new mutations through DNA errors that arise at random as cells divide or from environmental exposures. Under the stress of treatment, some cells acquire genetic changes to block, bypass or outlast the effects of therapy, which allow them to grow in number and thrive. In addition, acquired resistance to one drug may extend to other treatments in ways that are difficult to predict, leaving cancers “multidrug resistant,” says David Gewirtz, a pharmacologist and cancer researcher at VCU Massey Comprehensive Cancer Center in Richmond, Virginia.

Researchers have described many cellular mechanisms that play a role in treatment resistance. For instance, some cancers have proteins, called drug efflux pumps, that actively pump chemotherapy drugs out of the cells. Other cancers develop DNA repair mechanisms that allow affected cells to continue to rapidly divide despite treatment.

Gewirtz, who studies this complex and dynamic process, remains in awe that researchers have been so successful in thwarting cancer’s relentless drive to grow. “In my mind, the fact that we can cure some cancers is absolutely astonishing because there are so many ways that the tumors can escape, evade or develop resistance,” he says.

Gewirtz focuses much of his research efforts on senescent cancer cells, which are cells that stop dividing but remain in the body even after treatment. While this senescence was once considered permanent, evidence now suggests some senescent cancer cells can reawaken and begin growing again, spurring questions about their role in treatment resistance.

“Senescence allows them, in a sense, to hide from the cytotoxicity of the drugs by arresting,” or halting their development, Gewirtz says. “One might think that arresting is a desirable outcome if you can’t kill the tumor cells, but not if it allows or facilitates their recovery eventually.”

Gewirtz and other researchers are exploring whether a drug class—called senolytics—can eliminate these dormant cells. In 2022, he and colleagues published research in Molecular Pharmacology that showed an experimental agent called navitoclax could selectively eliminate senescent cells in head and neck cancer cell lines. When used with cisplatin, the drug also limited tumor progression and extended survival in mice compared with cisplatin alone.

Overcoming Cancer’s Superpower

Vadim Backman, a biomedical engineer at Northwestern University in Evanston, Illinois, has focused his research on understanding plasticity, a feature that gives cancer cells a unique and rapid capacity to change their identity and how they behave in the body, even as the underlying DNA sequence remains the same.

Likening the genome to a genetic “dictionary” that contains all our genes, Backman says that cells can gain different functions—for instance, as skin cells or neurons—by “reading” or expressing different “words” and stringing them together in different ways. Chromatin, a 3D genomic structure in the cell’s nucleus that determines which genes are suppressed or expressed, is essential to this process.

Backman’s team is exploring whether certain drugs can alter the organization of chromatin to change the way these cells “read” the genome by limiting the words that cancer cells can access.

His team published preclinical research July 22, 2025, in the Proceedings of the National Academy of Sciences that found an existing anti-inflammatory medicine used to treat arthritis called celecoxib could make tumors less likely to change their identity in response to chemotherapy. The approach hasn’t been tested in people, but the preclinical study showed that adding celecoxib to the chemotherapy paclitaxel slowed the growth of tumors in mice that had ovarian cancer. “It’s fairly early, but I think the proof of principle is there that we can chemically or biophysically affect the three-dimensional structure of the [cancer] genome and make it much less plastic, so then cancer cells become sitting ducks,” Backman says.

Harnessing Cancer’s Evolution

Gatenby has also studied whether altering treatment doses and schedules in advanced cancers could help lengthen treatment response. Traditionally, cancer treatment has followed a paradigm that calls for delivery of the maximum tolerated dose of a medicine to wipe out as many cancer cells as possible. This strategy, together with surgery, can effectively eliminate many cancers, especially early-stage disease, but it may not be as effective in advanced cancers that have already developed several resistance mechanisms, Gatenby says. In fact, high-dose treatment may eliminate sensitive cancer cells, leaving more resistant cells to divide and grow with less competition.

“The focus [in adaptive therapy] changes from trying to just kill as many of the sensitive cells as you can to controlling the resistant population, which ultimately determines outcomes,” Gatenby says. “Everything is about trying to keep that [resistant] population small.”

While more trials are needed to see how well this strategy works in clinical practice, a small study led by Gatenby’s team at Moffitt suggests this approach may help extend survival in people with metastatic prostate cancer. The study, which was published in 2022 in eLife, enrolled 33 men with metastatic castration-resistant prostate cancer who received a standard hormone therapy drug called abiraterone. Patients with this type of prostate cancer typically receive this therapy continuously until cancer progresses or side effects become intolerable. In the study, 17 participants stopped treatment when their prostate-specific antigen (PSA) levels—a marker of cancer’s activity—dropped by more than 50% from their baseline level. Treatment resumed when PSA levels rose to baseline once more.

Men who were treated using this adaptive approach had a median time to progression of 33.5 months, compared with 14.3 months for those who received continuous therapy. In addition, those who received the adaptive-therapy approach lived a median of 58.5 months, compared with 31.3 months in the other group. Participants who received the adaptive-therapy approach also only took treatment for about half the time, saving an estimated $70,000 per person per year, according to the study. “They’re really getting relatively small doses of [the] drug, expenses are reduced, and the quality of life is significantly improved,” Gatenby says.

Changing Treatment Before Progression

Other research is exploring the detection of treatment resistance almost as soon as it emerges—before cancer has had a chance to measurably progress—and then switching to new therapy.

Results from the SERENA-6 trial, published June 1, 2025, in the New England Journal of Medicine, assessed 315 women with advanced estrogen receptor-positive, HER2-negative breast cancer during first-line therapy. Half of the women switched to a different medication after blood tests suggested their cancer had developed an ESR1 mutation, a sign of treatment resistance. Researchers used blood tests to measure circulating tumor DNA (ctDNA) every two to three months, says Erica Mayer, a medical oncologist at Dana-Farber Cancer Institute in Boston and a researcher for the trial. “[We were] trying to identify this window when there may be an opportunity to provide an intervention that could delay or prevent progression,” Mayer says.

When blood tests revealed an ESR1 mutation, women either continued to receive standard first-line treatment—an aromatase inhibitor and a CDK4/6 inhibitor—plus a placebo, or they switched to a placebo, a CDK4/6 inhibitor and an experimental estrogen receptor degrader called camizestrant.

With about half of the participants being followed for about 12 months, the median progression-free survival in the camizestrant group was 16 months, compared with 9.2 months in the group of women with ESR1 mutations who continued standard treatment. The individuals who switched treatment sooner also showed improvements in quality of life.

“The patients who made this early switch had a substantial delay in developing symptoms like pain, fatigue, shortness of breath—the types of things we think of when we think of progressive cancer,” Mayer says. “So, by making that early switch, they were able to prolong the time when they felt well in comparison to people who didn’t make the switch. Patients felt better and could do more, and life was better for them.”

Applying New Ideas

Camizestrant is an investigational drug, which means it is only available through clinical trials, but the SERENA-6 trial results pave the way to consider more proactive ways to think about treatment resistance in hormone receptor-positive breast cancer, Mayer notes. In addition, participants in the trial who received ctDNA blood tests “were very interested to learn more about the real-time status of their cancer, this idea of new mutations and how to pick up on them early and apply a targeted intervention,” she says.

When non-small cell lung cancer is first diagnosed, oncologists order tumor testing to help identify appropriate first-line treatments, says Misako Nagasaka, an oncologist at UCI Health Chao Family Comprehensive Cancer Center in Orange, California. When patients experience tumor progression, they typically will get a biopsy, if it can be done safely, and a ctDNA test to look for changes that may explain resistance and point to alternate treatment options. “Unless we check, we will never know,” Nagasaka says. “I think there is definitely a role for at least making an attempt to check if a resistance mechanism has developed over the course of the treatment.”

Even if the testing fails to reveal any mutations that can be targeted with existing treatments, the biomarkers may help to expand patients’ clinical trial options and reveal other resistance mechanisms to study, Nagasaka says. “This is the way we move science [and cancer treatments] forward.”

Cancer Today magazine is free to cancer patients, survivors and caregivers who live in the U.S. Subscribe here to receive four issues per year.