Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer
Department of Pathology and Cell Biology, Columbia University Irving Medical Center, United States
Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, United States
Winship Cancer Institute at Emory University, Department of Hematology and Medical Oncology, United States
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Breast Cancer: Slowing the growth of drug-resistant tumors
Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer
insights into overcoming resistance in hormone receptor-positive breast cancer by demonstrating that sustained CDK4/6 inhibitor treatment, either alone or in combination with CDK2 inhibitors, significantly suppresses the growth of drug-resistant cancer cells. The findings are supported by
evidence from both in vitro cell line experiments and in vivo mouse models, highlighting the therapeutic potential of maintaining CDK4/6 inhibitors beyond disease progression. Additionally, the identification of cyclin E overexpression as a key driver of resistance offers a target that will be of value for future therapeutic strategies, potentially improving outcomes for patients with advanced breast cancer.
https://doi.org/10.7554/eLife.104545.3.sa0
: Findings that substantially advance our understanding of major research questions
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CDK4/6 inhibitors (CDK4/6i) with endocrine therapy are standard for hormone receptor-positive (HR
) metastatic breast cancer. However, most patients eventually develop resistance and discontinue treatment, and there is currently no consensus on effective second-line strategies. Using preclinical HR
human breast cancer models with acquired resistance to CDK4/6i, we demonstrate that maintaining CDK4/6i therapy, either alone or combined with CDK2 inhibitors (CDK2i), slows the growth of resistant tumors by prolonging G1 progression. Mechanistically, sustained CDK4/6 blockade in drug-resistant cells reduces E2F transcription and delays G1/S via a noncanonical, posttranslational regulation of retinoblastoma protein (Rb). Durable suppression of both CDK2 activity and growth of drug-resistant cells requires co-administration of CDK2i with CDK4/6i. Moreover, cyclin E overexpression drives resistance to the combination of CDK4/6i and CDK2i. These findings elucidate how continued CDK4/6 blockade constrains resistant tumors and support clinical strategies that maintain CDK4/6i while selectively incorporating CDK2i to overcome resistance.
Metastatic breast cancer remains a leading cause of cancer-related mortality in women globally (
). A key dysregulation in breast cancer involves the overactivation of cyclin-dependent kinases 4 and 6 (CDK4/6) (
). Active CDK4/6 phosphorylates the retinoblastoma protein (Rb), a crucial regulator that prevents cell-cycle initiation by sequestering E2F transcription factors (
). Rb phosphorylation results in the release of E2F, thereby promoting CDK2 activation and cell proliferation (
). Understanding this mechanism has driven significant advancements in therapeutic strategies, particularly for hormone receptor-positive (HR
)/human epidermal growth factor receptor 2-negative (HER2
) breast cancer, which constitutes approximately 70% of breast cancer cases (
). The current standard first-line treatment for HR
metastatic breast cancer is a combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) (
). Although this strategy has significantly improved patient outcomes, resistance remains a major challenge: approximately 30% of patients develop resistance within 2 years, and the majority ultimately relapse (
). Upon disease progression, CDK4/6i therapy is typically discontinued, often resulting in aggressive tumor regrowth and a lack of effective second-line treatment options.
While continuing ET after disease progression confers clinical benefit (
), the value of maintaining CDK4/6i treatment beyond progression remains elusive. Multiple ongoing and completed trials have evaluated continuing the FDA-approved CDK4/6 inhibitors, palbociclib, abemaciclib, and ribociclib, after progression (
). MAINTAIN and postMONARCH trials reported significantly improved progression-free survival (PFS) with continued CDK4/6i plus ET (
). Retrospective analyses likewise suggest that second-line CDK4/6i plus ET can outperform chemotherapy or ET alone in several settings (
). Safety appears comparable to or better than first-line trials, with no new toxicities and grade 3–4 events largely confined to expected hematologic adverse effects. In contrast, the PACE and PALMIRA trials did not demonstrate a PFS benefit for continuing CDK4/6i plus ET after progression (
). Overall, the evidence for CDK4/6i continuation beyond progression is encouraging but mixed, underscoring the need for mechanistic studies of CDK4/6i-resistant proliferation to guide post-progression treatment strategies for HR
Like CDK4/6, CDK2 also phosphorylates Rb before the G1/S transition (
). The relevance of CDK2 activation in CDK4/6i-resistant tumors highlights the potential of targeting CDK2 to overcome CDK4/6i resistance (
). Several clinical trials are currently evaluating CDK2 inhibitors (CDK2i) in patients who have progressed on CDK4/6i-based therapy, either as monotherapy or in combination with CDK4/6i, with or without ET (NCT05252416, NCT05735080). Determining the optimal strategy for incorporating CDK2i in treating HR
breast cancer that has developed drug resistance remains a critical question.
This study shows that, even in drug-resistant cells that remain proliferative, continued CDK4/6 inhibition results in ineffective Rb inactivation, thereby slowing E2F activation kinetics and prolonging the G1 phase. These data suggest that overall survival, rather than PFS, may serve as a more appropriate clinical trial endpoint. Moreover, our work highlights the therapeutic potential of combining CDK2i with CDK4/6i as an effective second-line strategy. Finally, we identify cyclin E overexpression as a key driver of resistance to this combination, offering mechanistic guidance for overcoming therapy resistance.
Maintaining CDK4/6i treatment attenuates the growth of drug-resistant cells by extending G1-phase progression
To evaluate the impact of continued CDK4/6i treatment in drug-resistant settings, we employed HR
breast cancer cell lines (MCF-7, T47D, and CAMA-1) and a triple-negative breast cancer cell line (MDA-MB-231), all of which have an intact Rb/E2F pathway. These cells were chronically exposed to palbociclib for over a month to induce drug resistance (
). We confirmed increased half-maximal inhibitory concentrations (IC50) for palbociclib in drug-resistant cells compared to parental cells (
). We maintained or withdrew CDK4/6i treatment in drug-resistant cells and monitored their cumulative proliferation alongside that of parental cells. Drug-resistant cells maintained on CDK4/6i exhibited significantly slower growth than those under other conditions (
). In contrast, resistant cells withdrawn from treatment grew at rates comparable to parental cells. Thus, despite the emergence of resistance, continued CDK4/6i treatment markedly suppresses the growth rate of drug-resistant cells.
Continuous CDK4/6i treatment suppresses the growth of drug-resistant cells.
) Schematic illustrating the establishment of CDK4/6i-resistant cells, either maint