Researchers from the IHU RespirERA have developed an innovative approach to overcome cancer cell resistance to conventional treatments by exploiting their molecular vulnerabilities and alternating between different types of cell death.
One of the major challenges in cancer therapy is the ability of tumor cells to develop resistance to drugs. Over time, some cells survive and adapt, making treatments progressively less effective.
These so-called Drug-Tolerant Persister (DTP) cells maintain a temporary but resilient state of resistance, often responsible for cancer relapse.
Until now, most therapeutic strategies have focused on triggering a programmed cell death mechanism known as apoptosis. However, some cancer cells manage to evade this process. To address this limitation, researchers explored an alternative pathway — necroptosis, another form of regulated cell death that can be activated when apoptosis fails.
A new strategy: alternating modes of cell death
The study revealed that cancer cells surviving an apoptosis-inducing treatment become, paradoxically, more sensitive to necroptosis.
In other words, their resistance to one type of therapy makes them vulnerable to another.
Based on this finding, researchers tested a sequential therapeutic strategy alternating between apoptotic and necroptotic treatments.
Results: a more effective therapeutic sequence
By alternating treatments that induce apoptosis and necroptosis, researchers observed a higher overall therapeutic efficacy compared to continuous treatments or drug holidays.
This alternating sequence limits tumor growth and prevents the re-emergence of resistant cells.
The optimal sequence involves first applying an apoptosis-inducing treatment to trigger cell vulnerability, followed by necroptosis to effectively eliminate the surviving cells.
These results open promising perspectives for the development of sequential cancer therapies.
Towards new strategies in cancer treatment
This research highlights an innovative way to bypass tumor resistance by turning a transient weakness into a therapeutic advantage.
Such an approach paves the way for more effective and adaptive treatments, tailored to the evolving behavior of cancer cells.
