| Peer-reviewed | Experimental study | Cells/Mice |
Researchers have provided evidence that a combination therapy against breast cancer is effective at slowing tumour growth, even after the cancer has become resistant to drugs.
The study, published today as a Reviewed Preprint in eLife, is described by the editors as a fundamental insight into overcoming treatment resistance in hormone receptor-positive (HR+) breast cancer. They describe the strength of evidence as compelling, highlighting the therapeutic potential of maintaining CDK4/6 inhibitor treatment when combating drug-resistant breast cancer. They also highlight that the identification of cyclin E overexpression as a key driver of resistance to combined CDK4/6 and CDK2 inhibitors offers a target for future therapeutic strategies, potentially improving outcomes for patients with an advanced form of the disease.
Breast cancer is a leading cause of cancer-related deaths worldwide, with HR+ breast cancer accounting for around 80% of cases, according to Cancer Research UK. This subtype is fueled by hormones such as estrogen and/or progesterone and involves the overactivation of cyclin-dependent kinases 4 and 6 (CDK4/6), which typically play a key role in regulating cell division.
“HR+ breast cancer is typically treated with CDK4/6 inhibitors in combination with hormone therapy to prevent its growth,” explains lead author Jessica Armand, a PhD student at the Herbert Irving Comprehensive Cancer Center and the Department of Pathology and Cell Biology, Columbia University Irving Medical Center (CUIMC), New York, US. “However, treatment resistance arises in most patients, meaning the cancer cells are able to evade the effects of CDK4/6 inhibitors, and there is no consensus on effective second-line therapies.”
Armand and colleagues set out to investigate whether continuing CDK4/6 inhibitor administration beyond resistance had therapeutic benefits. Using HR+ cancer cell lines and mouse models, they found that while CDK4/6 inhibitors could not completely block cancer cell growth, maintaining treatment significantly slowed progression by extending the time they spent in the G1 phase of the cell cycle – a preparatory step before cell division.
Building on their previous works, the team demonstrated that CDK4/6 inhibitors operate by activating the Retinoblastoma protein (Rb), which suppresses E2F transcription factors essential for cell division. In resistant cancer cells, Rb levels decrease due to protein degradation, allowing E2F activity to re-enable cell division. However, this alternative Rb inactivation mechanism through degradation results in ineffective E2F activation, significantly slowing cell-cycle progression. Continuing CDK4/6 inhibitor treatment leverages this ineffective Rb inactivation pathway to suppress the growth of HR+ breast cancer.
The researchers verified these findings in their HR+ cell lines as, when they removed Rb altogether, the cancer cells regained their ability to divide quickly, confirming its role in controlling tumour growth. Further validation came from a mouse model, where tumours under continued CDK4/6 inhibitor treatment grew significantly more slowly than untreated tumours. This growth suppression was observed when switching between different CDK4/6 inhibitors: palbociclib, ribociclib and abemaciclib.
Combining the inhibitors with the hormone therapy drug fulvestrant resulted in significantly stronger suppression of tumor growth by synergistically targeting E2F activation, even in cells less sensitive to fulvestrant. Furthermore, the researchers demonstrated that adding a CDK2 inhibitor, INX-315 – which targets another critical cell-cycle regulator downstream of E2F – enhanced the therapeutic effect, providing the most robust tumour suppression. While these findings suggest that the addition of CDK2 inhibitors holds great promise, the researchers emphasise that clinical trials are essential to validate the safety and efficacy of these strategies in patients.
Their study also revealed that cancer cells with high levels of cyclin E – a protein that accelerates CDK2 activity – can evade the effects of CDK4/6 and CDK2 inhibitors. By enhancing CDK2 activity, cyclin E effectively undermines the drugs’ inhibitory effects, making it a compelling target for future research aimed at combating resistance in HR+ breast cancer.
“Our work offers insights that support the continued use of CDK4/6 inhibitors and endocrine therapy in patients with resistant HR+ breast cancer, and emphasises the necessity of targeting multiple pathways simultaneously to overcome treatment failure,” concludes senior author Hee Won Yang, an assistant professor at the Herbert Irving Comprehensive Cancer Center and the Department of Pathology and Cell Biology, CUIMC. “In addition, we’ve highlighted the critical role of cyclin E overexpression in driving resistance to CDK4/6 and CDK2 dual inhibition, which warrants further investigation as a potential target for treatment.”
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