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A non-canonical function of the tyrosine degradation enzyme FAH drives CDK4/6 inhibitor resistance in breast cancer I

ABSTRACT: Resistance to standard-of-care therapies remains a major clinical challenge in the treatment of the most common breast cancer, the hormone receptor–positive (HR+) subtype. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors improve outcomes in early-stage HR+ disease, yet many patients relapse. Resistance mechanisms of relapsed tumors include genetic alterations, but in many cases no genetic drivers are identified. Here, we investigated mechanisms underlying resistance to CDK4/6 inhibitors using breast cancer patient-derived models and tumors. We identified an unexpected, non-catalytic nuclear function of fumarylacetoacetate hydrolase (FAH), an enzyme in the tyrosine catabolism pathway, as a driver of resistance. FAH translocated to the nucleus upon CDK4/6 inhibition, where it interacted with cyclin-dependent kinase 9 (CDK9), and promoted resistance. Nuclear FAH was enriched in tumors from relapsed patients, and inhibition of CDK9 reversed FAH-mediated resistance. These findings establish nuclear FAH as a biomarker of resistance and revealed CDK9 as a therapeutic vulnerability in CDK4/6 inhibitor-resistant HR+ breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE330516 | GEO | 2026/07/30

REPOSITORIES: GEO

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A non-canonical function of the tyrosine degradation enzyme FAH drives CDK4/6 inhibitor resistance in breast cancer II

Project description:Resistance to standard-of-care therapies remains a major clinical challenge in the treatment of the most common breast cancer, the hormone receptor–positive (HR+) subtype. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors improve outcomes in early-stage HR+ disease, yet many patients relapse. Resistance mechanisms of relapsed tumors include genetic alterations, but in many cases no genetic drivers are identified. Here, we investigated mechanisms underlying resistance to CDK4/6 inhibitors using breast cancer patient-derived models and tumors. We identified an unexpected, non-catalytic nuclear function of fumarylacetoacetate hydrolase (FAH), an enzyme in the tyrosine catabolism pathway, as a driver of resistance. FAH translocated to the nucleus upon CDK4/6 inhibition, where it interacted with cyclin-dependent kinase 9 (CDK9), and promoted resistance. Nuclear FAH was enriched in tumors from relapsed patients, and inhibition of CDK9 reversed FAH-mediated resistance. These findings establish nuclear FAH as a biomarker of resistance and revealed CDK9 as a therapeutic vulnerability in CDK4/6 inhibitor-resistant HR+ breast cancer.

2026-07-30 | GSE330518 | GEO

Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer

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2024-10-10 | GSE279160 | GEO

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2025-12-15 | PXD052290 | Pride

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Single-Cell RNA Sequencing Identifies Molecular Biomarkers Predicting Late Progression to CDK4/6 Inhibition in Patients with HR+/HER2- Metastatic Breast Cancer [tissue]

2025-02-18 | GSE274139 | GEO

Dual targeting CDK4/6 and CDK7 augments tumor response and anti-tumor immunity in breast cancer

Project description:CDK4/6 inhibitors (CDK4/6i) have significantly improved the prognosis for hormone-positive (HR+) breast cancer patients. However, the emergence of drug resistance severely limits their long-term efficacy, and CDK4/6i monotherapy remains largely ineffective against triple-negative breast cancer (TNBC). Here, we demonstrate that combining CDK4/6i with CDK7 inhibitors (CDK7i) offers a promising therapeutic strategy to overcome resistance in both HR+ breast cancer and TNBC. Kinetic analyses reveal that CDK7i primarily targets RNA polymerase II-mediated transcription, a key driver of CDK4/6i resistance by amplifying E2F activity following the degradation of the retinoblastoma protein. Consequently, the combination of CDK4/6i and CDK7i synergistically suppresses E2F activity and inhibits the growth of drug-resistant tumors. Furthermore, this combination stimulates immune response pathways and cytokine production in cancer cells, enhancing anti-tumor immunity. These findings provide critical insights into evolving CDK inhibition strategies and highlight the therapeutic application of CDK7i in breast cancer management.

2024-11-07 | GSE281158 | GEO

FOXA1 phosphorylation by CDK4 prevents activation of novel chromatin regions and HER2 expression in breast cancer

Project description:Cyclin Dependent Kinase 4/6 inhibitors induce transcription in breast tumors via FOXA1 chromatin binding. The use of Cyclin Dependent Kinase 4/6 inhibitors (CDK4/6i) induce transcription in breast tumors. The control mechanism of such genomic changes and their physiological relevance are not elucidated yet. Now, we identified chromatin activation of tumors treated with CDK4/6i. These chromatin changes induce an increase of HER2 expression and signaling. Mechanically, our study demonstrates that FOXA1 is a new substrate of CDK4 and that its phosphorylation limits the binding of FOXA1 to conventional chromatin regions. Moreover, when patients are treated with CDK4/6i, a dephosphorylated FOXA1 binds to additional chromatin regions. By doing so, FOXA1 leads to an increase of HER2 expression and of the activation of HER2-MEK-ERK pathway in breast cancer patients. Accordingly, we might envision a clinical benefit of adding antiHER2 therapy to delay development of resistance and therefore, to prolong PFS in patients yet receiving CDK4/6i.

2023-09-01 | GSE231544 | GEO

Abemaciclib differentially reshapes the immunopeptidome of breast cancer subtypes

Project description:The cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) Abemaciclib has demonstrated transformative potential in the treatment of hormone receptor-positive (HR+) breast cancer. Beyond its established role in cell cycle arrest, we reveal its capacity to enhance tumor immunogenicity by remodeling the immunopeptidome. Using a proteogenomic approach, we analyzed the antigenic repertoire of HR+ and triple-negative breast cancer (TNBC) models following Abemaciclib treatment. Our findings highlight a substantial increase in MHC-I presentation and antigen diversity, particularly in HR+ cells. This effect is mediated through Rb-dependent transcriptional and epigenetic reprogramming involving bromodomain and extraterminal (BET) proteins. Furthermore, we identified novel abemaciclib-induced neoantigens derived from allegedly non-coding genomic regions with therapeutic potential for CDK4/6i-combinational immunotherapies. Our data provide a molecular rationale for the superior efficacy of Abemaciclib in HR+ breast cancers. They also suggest that treatment with Abemaciclib could synergize with immunotherapies targeting CDK4/6i-induced tumor antigens.

2026-02-25 | PXD060684 | Pride

Proteomic analysis of CDK4/6 inhibition in T47D cells

Project description:CDK4/6 inhibitors have emerged in combination with hormone therapy as an effective treatment for HR+/HER2- breast cancer. Despite the clinical success of these drugs, challenges such as varied patient response and acquired resistance remain a significant treatment barrier. To better understand the mechanisms by which breast cancer cells respond to CDK4/6 inhibition, we conducted a multi-omics analysis in T-47D breast cancer cells profiling Palbociclib-induced changes at the gene expression, alternative splicing, and proteomic levels. We report that cell division and proliferation-related genes are often downregulated and also subject to alternative splicing changes. Additionally, we find an upregulation of estrogen response-related genes, suggesting negative feedback between CDK4/6 and upstream hormone signaling. Intriguingly, we observe an upregulation of Cyclin D1 (consistent with previous literature) but not Cyclin D3, indicating distinct and specific roles for these cyclins in the Palbociclib response. Finally, we observe that Palbociclib broadly downregulates genes essential for cell proliferation and survival, and that co-targeting CDK7 in combination additively affects proliferation, suggesting combination strategies which might be used to achieve improved therapeutic benefit. Our findings reveal both the broad patterns and specific gene- and protein-level changes that result from Palbociclib treatment, providing a key resource in understanding the response to CDK4/6 inhibitors for researchers and clinicians to improve breast cancer treatments and expand the use of CDK4/6 inhibitors to other cancers.

2026-02-23 | PXD064572 | Pride

Characterizing of Breast Cancer translational PEARL clinical trial

Project description:Introduction In HR+/HER2- metastatic breast cancer (MBC) is imperative to identify patients who respond poorly to CDK4/6i and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting but further validation is needed. Methods We performed mRNA gene expression profiling and correlation with progression-free-survival (PFS) on 455 tumor samples included in the phase III PEARL study, that assigned HR+/HER2- MBC patients to receive palbociclib+ET vs capecitabine. ER+/HER2- breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET. Results Non-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4months (m) with palbociclib+ET and 9.3m with capecitabine; HR:4.16, adjusted p-value<0.0001. Tumors with high CCNE1 expression (above median) had also worse median PFS with palbociclib+ET (6.2m) than with capecitabine (9.3m); HR:1.55, adjusted p-value=0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile) we found higher levels of Polo Like Kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2- cell line models we show that PLK1 inhibition reverses resistance to palbociclib+ET. Conclusion We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i.

2023-01-26 | GSE223700 | GEO

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