Few moments in cancer treatment are harder for a patient to understand than hearing that a therapy that had been working no longer is. Scans may have shown improvement for months before the progress suddenly stalls. A tumor that had been shrinking begins to grow again. The drug hasn't changed, and neither has the diagnosis. So, what happened?
Often, the tumor itself has changed. Cancer cells can adapt to the pressure created by treatment, finding new ways to survive even after a therapy blocks the pathway they once depended on. Understanding how that happens is a major focus of Dr. Elsa R. Flores and her work at the Moffitt Cancer Center in Tampa, Florida.
Her research looks beyond the individual drug that stopped working to the genetic and cellular machinery that allowed the cancer to escape it. Much of that work has centered on one particularly important family of genes: p53.
The Gene at the Center of the Problem
TP53 has carried a frustrating label in cancer research for decades: undruggable. The problem isn't a lack of effort. It has more to do with what the gene actually does.
TP53 produces p53, a transcription factor that helps control which genes are switched on and off inside a cell. In doing so, it influences some of the cell's most fundamental behaviors, including whether a damaged cell repairs itself, stops dividing, or dies.
Many drugs are designed around a relatively straightforward target, such as an enzyme or receptor that can be blocked. p53 doesn't offer researchers such an obvious point of attack. When its function is lost or altered, a critical safeguard against abnormal cell growth disappears, but restoring that safeguard directly has proved difficult.
That creates a problem for cancer treatment because tumors with TP53 alterations can be more aggressive and may eventually find ways around therapy. Research from the laboratory of Elsa R. Flores has taken a different approach to that challenge. Rather than focusing only on how to target p53 itself, Flores and her team have spent more than two decades studying the rest of the p53 family and the pathways these genes control.
The idea is that even when the most obvious target can't be reached directly, something else in the same biological system may offer another way in.
Looking Beyond p53
p53 doesn't work alone. It has two close relatives, p63 and p73, and research from the Flores laboratory helped establish that both genes — along with their different isoforms — can suppress tumor formation and metastasis across several types of tissue.
This changed how researchers think about the p53 family. Instead of viewing p53 as a single gatekeeper whose loss leaves no obvious alternative, researchers can understand the family as a larger network. Other members of that network may still be active even when p53 itself has been lost or mutated.
Flores's research has also shown that p63 and p73 do much more than control cell division. p63 and its isoforms (TA and ∆N) help maintain adult stem cell populations and regulate metabolic programs associated with longevity. Members of the p53 family are also involved in germline embryonic stem cells and in generating induced pluripotent stem cells.
Their influence extends into another layer of cellular regulation as well. Some of the family's tumor-suppressive activity works through genes involved in microRNA biogenesis, giving these proteins a role in determining how other genetic messages are regulated inside the cell.
Those connections become particularly important when researchers are trying to understand therapy resistance. A tumor's ability to change its metabolism, alter gene activity, or draw on a resistant population of cells can give it new ways to survive when a treatment closes off the pathway it had been using.
How a Tumor Finds Another Route
One example from the Flores laboratory involves long non-coding RNAs. Unlike more familiar forms of RNA that carry instructions for making proteins, these molecules don't become proteins themselves. Instead, they can help regulate which genes and signaling pathways are active.
The Flores laboratory identified an oncogenic long non-coding RNA regulated by TAp63 and found that targeting it could interfere with Akt activation, an important cell-survival signaling protein. The work, published in Nature Communications in 2020, also connected that pathway to resistance across multiple targeted cancer therapies.
It offers a useful way to think about how resistance develops. A drug may successfully block one route a tumor uses to survive, only for the cancer to begin relying more heavily on another. Akt is one of the survival pathways cancers can use in that way, and directly targeting it has presented its own challenges. Targeting a regulatory mechanism that helps activate the pathway could offer another approach.
Related research from the Flores laboratory has examined the p53 family's relationship with super enhancers, regions of DNA that can drive unusually high levels of gene activity. The lab published that work in Nature Communications in 2022.
Taken together, these findings show why therapy resistance is more complicated than a tumor simply acquiring another mutation. Cancer cells can reorganize the systems controlling gene activity and redirect signals around the pathway a treatment was designed to block. You can find more of Flores's work on these mechanisms in her published cancer research.
Resistance Doesn't Stop at the Cancer Cell
The cancer cell itself is only part of the picture. A tumor exists within a larger environment of immune cells, nutrients, signaling molecules, and surrounding tissue, and changes in that environment can also affect how well treatment works.
As contact principal investigator on an NCI-funded Program Project Grant, Dr. Elsa R. Flores leads research into metabolic vulnerabilities in lung cancer, including tumors that have already developed resistance to therapy.
Part of that work examines p53-mutant cancers and the role TAp73 may play in anti-tumor immunity by affecting lipid metabolism in the tumor microenvironment. The question is whether tumors can change the metabolic conditions around them in ways that make it harder for the immune system to respond effectively.
Researchers are now exploring those pathways as potential therapeutic targets in p53-mutant lung adenocarcinoma, including cancers that have become resistant to KRAS inhibitors.
That opens up a different way of approaching the problem. If part of the tumor's resistance comes from changes it creates in the tissue and immune environment around itself, researchers don't necessarily have to respond by designing another version of the same drug. They may be able to target the conditions that are helping the tumor survive.
Watching Resistance as It Develops
Understanding therapy resistance also depends on watching it develop over time. That requires research models that can separate the effects of closely related genes and tools that can find patterns across large numbers of tumor samples.
The Flores laboratory has developed isoform-specific conditional knockout mouse models that allow researchers to switch off individual members and variants of the p53 family. The team also works with freshly removed patient tumor samples available through Moffitt Cancer Center, an NCI-designated comprehensive cancer center.
More recently, that work has expanded into computational methods. Through an NCI T32 training program designed to bring cancer biology and data science together, the laboratory contributed to the development of GLASS-AI, an artificial intelligence tool used to grade preclinical lung cancer models and support molecular analysis of cancer progression and therapy resistance. The work was described in npj Precision Oncology in 2023.
For researchers, tools like these can make patterns easier to see across many samples and stages of disease. Tumor tissue can be difficult to grade consistently at scale through human observation alone, particularly when the goal is to understand subtle changes taking place as a cancer progresses or responds to treatment.
That makes better measurement part of the resistance problem itself. Researchers need to understand not only which changes occur, but when they occur and how those changes relate to when treatment stops working. Additional publications from Elsa R. Flores, PhD, cover this work across cancer biology, genetics, and therapy resistance.
Finding Another Way into an "Undruggable" Cancer
One of the broader ideas running through Flores's research is that an undruggable target doesn't necessarily leave researchers without options.
If a protein can't be targeted directly, scientists can look at the systems surrounding it. That might mean a non-coding RNA it regulates, a metabolic pathway it influences, or an immune response that changes when the gene stops functioning normally. Each creates another potential point where researchers may be able to intervene.
The same approach could eventually prove useful beyond the p53 family. Other tumor suppressor genes and cancer pathways have also resisted conventional drug development, and understanding the wider networks around those targets may reveal vulnerabilities that aren't obvious when researchers look at the gene alone.
None of that makes the process fast. A discovery made in a mouse model or patient tissue sample can take years of additional research before it leads to a clinical trial, much less an approved treatment. The work depends on infrastructure that patients rarely see, including specialized animal models, access to tumor samples, and collaborations between cancer biologists, clinicians, and data scientists.
But it changes how researchers can think about the moment when a treatment stops working.
A resistant tumor hasn't simply become immune to treatment. Something changed that allowed it to survive. The cancer may have activated another signaling pathway, altered its metabolism, changed its surrounding environment, or relied on a population of cells better equipped to withstand the drug.
The challenge for researchers such as Dr. Elsa R. Flores is to find that change. Once the mechanism behind resistance becomes visible, it becomes something scientists can study — and potentially something a future treatment can interrupt.
About the Author
Elsa R. Flores, PhD, is a Senior Member in the Department of Molecular Oncology at Moffitt Cancer Center, with secondary appointments in Cutaneous Oncology and Thoracic Oncology. She is also a professor in the Departments of Oncologic Sciences and Biomedical Engineering at the University of South Florida Health Morsani College of Medicine.
Her research focuses on the p53 family of tumor suppressor genes and the molecular pathways involved in cancer development, metastasis, metabolism, and therapy resistance. Her work has been recognized with the NCI Outstanding Investigator Award, which she held from 2016 to 2024, the Kaul Foundation Endowed Chair, and selection as a V Foundation All Star for 2026 through 2031. Earlier in her career, she was named a Rita Allen Foundation Scholar and an American Cancer Society Research Scholar.
