Cancer cells reprogram their metabolism to escape the drug
For generations, cancer has revealed itself as a shape-shifter — adapting to whatever we throw at it, finding new pathways to survive. Researchers at the University of Barcelona have now mapped one such escape route in colorectal cancer, showing precisely how cells outwit the drug palbociclib by rewiring their metabolism, and demonstrating that a second drug, telaglenastat, can close that exit. The discovery matters not only for the patients it may one day reach, but for what it represents: a shift from guesswork toward a principled understanding of resistance itself.
- Colorectal cancer — the third most common cancer in the world — has long resisted palbociclib, a drug that works well against breast cancer, leaving researchers searching for answers.
- The culprit turns out to be metabolic cunning: surviving cancer cells ramp up glutamine consumption and mitochondrial activity, effectively rerouting around the drug's blockade.
- Barcelona researchers mapped this escape mechanism with precision, identifying glutaminase as the critical enzyme enabling the cells' survival strategy.
- Telaglenastat, a glutaminase inhibitor, was tested alongside palbociclib and produced a synergistic effect — the combination dismantled both the division machinery and the metabolic lifeline cancer cells depend on.
- Preclinical results published in Oncogene now point toward clinical trials, where this targeted, mechanism-driven combination could be tested in human patients for the first time.
Colorectal cancer has long resisted the drug palbociclib, which is already approved for advanced breast cancer and works by blocking the CDK4 and CDK6 proteins that cancer cells need to divide. The problem is that colorectal cancer cells don't simply succumb — they adapt. When exposed to palbociclib, surviving cells reprogram their metabolism, leaning heavily on glutamine and boosting mitochondrial activity to stay alive. This metabolic escape has made the drug largely ineffective against the disease.
Marta Cascante, a biochemistry professor at the University of Barcelona and a leader in metabolomics research, led a team that set out to map exactly what was happening inside these resistant cells. Working alongside colleagues including Timothy Thomson at the Molecular Biology Institute of Barcelona, they identified the key enzyme driving the escape: glutaminase, which converts glutamine into glutamate and fuels the cells' survival. Block that enzyme, they reasoned, and you close the exit.
Telaglenastat does precisely that. When the Barcelona team combined it with palbociclib in laboratory and animal models, the results were striking — the two drugs worked in concert, each targeting a different vulnerability, producing a synergistic effect far more powerful than either alone. The findings, published in Oncogene, represent something rarer than a new drug: a mechanistic explanation of resistance, followed by a rationally chosen solution.
Cascante and her colleagues now argue the combination warrants clinical trials in human patients. With colorectal cancer ranking among the most common and deadly cancers worldwide — affecting primarily people over fifty — a treatment capable of overcoming drug resistance could meaningfully shift outcomes. The question now passes to clinicians.
Colorectal cancer kills tens of thousands of people each year, and for decades the standard response has been surgery, chemotherapy, radiation, or biological drugs — each with their own limits and side effects. Now researchers at the University of Barcelona have identified why one promising drug fails against this disease, and more importantly, what to pair it with to make it work.
The drug in question is palbociclib, already approved for treating advanced breast cancer. It works by blocking two proteins called CDK4 and CDK6, which cancer cells need to divide and grow. When you starve a cell of those proteins, you slow its multiplication. The problem is that colorectal cancer cells are clever. When exposed to palbociclib, the cells that survive don't simply accept defeat. Instead, they reprogram their metabolism — the chemical machinery that keeps them alive. Specifically, they ramp up their consumption of glutamine, an amino acid, and boost their mitochondrial activity. This metabolic shift is the escape route. The cancer cells adapt, survive, and the drug stops working.
Marta Cascante, a professor of biochemistry at the University of Barcelona and a pioneer in metabolomics research, led a team that decided to map exactly what was happening inside these resistant cells. Working with colleagues including Timothy Thomson at the Molecular Biology Institute of Barcelona, they exposed colorectal cancer cells to palbociclib and watched the metabolic changes unfold. What they found was precise and actionable: the surviving cells were leaning heavily on an enzyme called glutaminase, which converts glutamine into glutamate. If you could block that enzyme, you could prevent the metabolic escape.
That's where telaglenastat enters the picture. It's a drug designed to do exactly that — inhibit glutaminase and cut off the cancer cell's ability to process glutamine the way it needs to. The Barcelona team tested what happened when they combined palbociclib with telaglenastat. The results, published in the journal Oncogene, showed something striking: the two drugs work in concert. Palbociclib blocks cell division proteins; telaglenastat blocks the metabolic adaptation that allows cells to survive palbociclib. Together, they create what researchers call a synergistic effect — the combination is more powerful than either drug alone. In laboratory models and in animal studies, the pairing reduced tumor growth far more effectively than palbociclib by itself.
What makes this finding significant is that it moves beyond trial-and-error drug combinations. The Barcelona team identified the specific mechanism of resistance, then selected a drug that directly counteracts it. Cascante and her colleagues stress that these preclinical results justify moving toward clinical trials in human patients. Colorectal cancer is the third most common cancer worldwide, and most cases occur in people over fifty. A treatment that could overcome drug resistance would change outcomes for thousands of patients. The work now sits in the hands of clinicians who will decide whether to test this combination in people.
Citações Notáveis
Palbociclib and telaglenastat induce complementary metabolic responses, making them particularly well suited to counteract the metabolic reprogramming caused by the other drug.— Míriam Tarrado and Carles Foguet, lead researchers
These findings justify a promising proposal to use this drug combination in clinical settings.— University of Barcelona research team
A Conversa do Hearth Outra perspectiva sobre a história
Why does palbociclib work initially if cancer cells are going to adapt anyway?
It does work — it slows growth. But cancer cells are under intense pressure to survive, and they have metabolic flexibility. When you block their division machinery, they don't die; they shift to a different survival strategy. That's the adaptation.
And telaglenastat specifically targets that adaptation?
Exactly. It blocks glutaminase, which is the enzyme the surviving cells depend on after palbociclib exposure. The two drugs address different vulnerabilities in the same cell.
Is this combination already being used in patients?
No, this is preclinical work — laboratory and animal models. The next step would be clinical trials in humans. That's why the researchers emphasize that their findings justify moving in that direction.
How common is this kind of metabolic resistance in cancer?
It's increasingly recognized as a major problem. Cancer cells are metabolically flexible in ways that normal cells aren't. Many drugs fail not because they don't work initially, but because resistant cells find new metabolic pathways to survive.
So the real innovation here is identifying the mechanism first, then the drug?
Yes. Instead of randomly combining drugs and hoping, they mapped the resistance mechanism and selected a drug that directly blocks it. That's a more rational approach to combination therapy.