RANK expression and Luminal BC response to CDK4/6 inhibitors
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE224435 | GEO | 2023/06/09
REPOSITORIES: GEO
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Project description:CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90/CDC37 complex. In contrast, CDK4/6i and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.
2022-02-16 | PXD023137 | Pride
Project description:Purpose: Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER) positive (ER+) breast cancer (BC). Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine resistant ER+ BC models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ BC. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ BC remain elusive. Herein, we sought to unravel these mechanisms. Experimental Design: We conducted multi-omic analyses in ER+ BC models in vitro and in vivo including models with different genetic backgrounds. We also performed genome wide CRISPR knock-out library screens to identify potential therapeutic vulnerabilities in CDK4/6i resistance models. Results: We found that the on-target anti-tumor effects of CDK7 inhibition in ER+ BC are in part p53 dependent, involve cell-cycle inhibition and suppression of c-Myc. Moreover, CDK7 inhibition exhibited cytotoxic effects, distinctive from the cytostatic nature of ETs and CDK4/6i. CDK7 inhibition resulted in suppression of ER phosphorylation at S118, however, long-term CDK7 inhibition resulted in increased ER signaling, supporting the combination of ET with a CDK7i. Lastly, genome wide CRISPR/Cas9 screens identified CDK7 and MYC signaling as putative vulnerabilities in CDK4/6i resistance, and CDK7 inhibition effectively inhibited CDK4/6i resistant models. Conclusions: Taken together, these findings support the clinical investigation of selective CDK7 inhibition combined with ET to overcome treatment resistance in ER+ BC. In addition, our study highlights the potential of increased c-Myc activity and intact p53 as predictors for sensitivity to CDK7 inhibitor-based treatments.
2024-02-12 | GSE230362 | GEO
Project description:Despite overall good prognosis associated to thyroid cancer, poorly differentiated carcinomas (PDTC) and anaplastic carcinomas (ATC) represent major clinical challenges. We have shown that the presence of active T172-phosphorylated CDK4 predicts sensitivity to CDK4/6 inhibitory drugs (CDK4/6i) including palbociclib. Here, CDK4 phosphorylation was detected in all well-differentiated thyoid carcinomas (n=29), 19/20 PDTC, 16/23 ATC, and 18/21 thyroid cancer cell lines including 11 ATC-derived ones. The cell lines lacking CDK4 phosphorylation were insensitive to CDK4/6i. RNA-sequencing and immunohistochemistry revealed that tumors and cell lines without phosphorylated CDK4 presented very high p16CDKN2A levels that were associated with proliferative activity. One of the main mechanisms of resistance to CDK4/6i is RB1 defects or inactivation. RB1 mutations were present in the 3 insensitive cell lines but were not found in 5 of the 7 tumors without phosphorylated CDK4. p16/KI67 immunohistochemistry and a previously developed 11-gene signature identified the likely insensitive tumors and cell lines lacking CDK4 phosphorylation. In cell lines, palbociclib synergized with dabrafenib/trametinib, completely and irreversibly arresting proliferation. The combined drugs prevented resistance mechanisms induced by palbociclib, most notably Cyclin E1-CDK2 activation and a paradoxical stabilization of phosphorylated CDK4 complexes. Our study supports the evaluation of CDK4/6i for ATC/PDTC treatment, including in combination with MEK/BRAF inhibitors.
2023-10-10 | GSE235468 | GEO
Project description:Ovarian cancer is insensitive to immunotherapy and has a high mortality rate. CDK4/6 inhibitors (CDK4/6i) regulate the tumor microenvironment and play an antitumor role. Our previous research demonstrated that lymphocyte aggregation (tertiary lymphoid structures, TLS) was observed after CDK4/6i treatment. This may explain the synergistic action of CDK4/6i with the anti-PD1 antibody. However, the key mechanism by which CDK4/6i promotes TLS formation has not been elucidated. We examine the link between TLS and prognosis. Animal models and high-throughput sequencing were used to explore the potential mechanism by which CDK4/6i promotes TLS formation. Our results showed the presence of TLSs was associated with a favorable prognosis for ovarian cancer. CDK4/6i promoted TLS formation and enhanced the immunotherapeutic effect of the anti-PD1 antibody. The potential mechanism of CDK4/6i affecting the formation of TLS may be through modulating SCD1 and its regulatory molecules ATF3 and CCL4. Our findings provide a theoretical basis for the application of CDK4/6i in ovarian cancer.
2023-10-12 | GSE234106 | GEO
Project description:CDK4/6 inhibitors are highly effective against ER+/HER2- breast cancer (BC); however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6 inhibitors may lead to the identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes. Parental BC cells and their endocrine-resistant derivatives (EndoR) were used in this study. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation-resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. We found that parental and EndoR BC lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high Interferon (IFN) signaling and reduced sensitivity to CDK4/6 inhibitors, thus an ‘IFN-Related Palbociclib-Resistance Signature’ (IRPS) was derived. In two neoadjuvant trials of a CDK4/6 inhibitor plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6 inhibition. PalboR derivatives displayed a dramatic activation of IFN/STAT1-signaling compared to their short-term treated or untreated counterparts. In primary ER+/HER2- tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis. Our study demonstrates that aberrant IFN-signaling is associated with intrinsic resistance to CDK4/6 inhibitors. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN-pathway, which warrants additional studies to clarify its involvement in resistance to CDK4/6 inhibitors.
2021-12-04 | GSE150997 | GEO
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
Project description:CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identified protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout (RBKO) breast cancer cells. Inhibition of PRMT5 blocked the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RBKO cells. Proteomics analysis uncovered fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 resulted in dissociation of FUS from RNA polymerase II (Pol II), which led to Ser2 Pol II hyperphosphorylation, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibited growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight the potential of dual ER and PRMT5 blockade as a novel therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.
2023-07-11 | GSE236499 | GEO
Project description:CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identified protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout (RBKO) breast cancer cells. Inhibition of PRMT5 blocked the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RBKO cells. Proteomics analysis uncovered fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 resulted in dissociation of FUS from RNA polymerase II (Pol II), which led to Ser2 Pol II hyperphosphorylation, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibited growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight the potential of dual ER and PRMT5 blockade as a novel therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.
2023-07-11 | GSE236497 | GEO
Project description:CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identified protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout (RBKO) breast cancer cells. Inhibition of PRMT5 blocked the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RBKO cells. Proteomics analysis uncovered fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 resulted in dissociation of FUS from RNA polymerase II (Pol II), which led to Ser2 Pol II hyperphosphorylation, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibited growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight the potential of dual ER and PRMT5 blockade as a novel therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.
2023-07-11 | GSE236498 | GEO
Project description:CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identified protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout (RBKO) breast cancer cells. Inhibition of PRMT5 blocked the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RBKO cells. Proteomics analysis uncovered fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 resulted in dissociation of FUS from RNA polymerase II (Pol II), which led to Ser2 Pol II hyperphosphorylation, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibited growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight the potential of dual ER and PRMT5 blockade as a novel therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.
2023-07-11 | GSE236496 | GEO