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For patients with advanced or metastatic ER+ breast cancer, cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6 inhibitors) are now the standard of care and, in recent years, have significantly improved treatment outcomes.  However, for about 30 per cent of patients, these treatments eventually stop working.  When the cancer becomes resistant and spreads to other parts of the body, there are currently no effective second-line treatment options—making drug resistance a major and growing challenge in breast cancer care.

SAiGENCI’s and her team are working to understand why this resistance develops and how it might be overcome.  Their research points to an unexpected culprit:  so-called “jumping genes,” or transposable elements.  These ancient fragments of viral DNA make up nearly half of the human genome.  Once believed to be inactive, they are now known to play a role in cancer by switching on genes that help tumours grow and evade treatment.

The team has found evidence that in CDK4/6 inhibitor–resistant breast cancer, these jumping genes may become reactivated, driving disease progression.  Encouragingly, their work also suggests a potential way to switch them off.

The solution may lie in p53, a powerful tumour-suppressor protein often described as the “guardian of the genome".  Dr Achinger-Kawecka and colleagues have shown that drugs designed to reactivate p53 could suppress these harmful genetic elements and restore the cancer’s sensitivity to CDK4/6 inhibitors.

Using laboratory models developed from tumour samples of ER+ breast cancer patients whose disease returned after CDK4/6 inhibitor therapy, the researchers will test whether p53-activating drugs can reverse treatment resistance.  If successful, this approach could allow patients to benefit from their existing therapies for longer—delaying disease progression and improving quality of life.