CDK4/6 inhibitors plus RANKL inhibitors in syngeneic TNBC model
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE277614 | GEO | 2025/05/20
REPOSITORIES: GEO
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Project description:CDK4/6i alone have proven to be largely ineffective in TNBC, even in the presence of functional retinoblastoma protein (pRB). In this study, we investigated the role of the RANK pathway in the response to CDK4/6i in pRB-proficient TNBC. Transcriptomic analysis of xenografts revealed that combining CDK4/6i with RANKLi more effectively arrested the cell cycle.
2025-05-20 | GSE277615 | GEO
Project description:CDK4/6 inhibitors plus RANKL inhibitors in syngeneic TNBC model
| PRJNA1162907 | ENA
Project description:Combining CDK4/6 inhibitors (CDK4/6i) with endocrine therapy has proven clinically effective and represents now the first-line treatment for advanced Luminal Breast Cancer (LBC) patients. However, resistance to CDK4/6i almost invariably arises in these patients, emphasising the critical need to comprehend these mechanisms and develop new strategies to overcome resistance. We report on the generation and characterisation of a LBC PDX displaying acquired resistance to CDK4/6i palbociclib. Treating a sensitive luminal BC PDX with the CDK4/6i palbociclib revealed that, despite initial tumour shrinkage, some tumours might eventually regrow under drug treatment. RNA sequencing, followed by gene set enrichment analyses, unveiled that this PDX have become refractory to CDK4/6i, both at biological and molecular level.
2024-11-18 | E-MTAB-14085 | biostudies-arrayexpress
Project description:The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) has significantly improved outcomes for patients with hormone receptor-positive (HR+) metastatic breast cancer. However, most patients eventually develop resistance, leading to treatment discontinuation. The therapeutic benefits of maintaining CDK4/6i or transitioning to CDK2 inhibitors (CDK2i) beyond disease progression remain unclear. Here, we show that maintaining CDK4/6i and ET or combining them with CDK2i effectively suppresses the growth of drug-resistant HR+ breast cancer cells by prolonging G1-phase progression. CDK4/6i maintenance triggers a non-canonical pathway for Rb inactivation through post-translational degradation, resulting in attenuated E2F activity and slowed G1 progression. ET further augments this effect by inhibiting c-Myc-mediated E2F amplification. Although the maintenance of CDK4/6i and ET outperforms CDK2i with ET, the triple combination of CDK4/6i, CDK2i, and ET most effectively suppresses both E2F activity and tumor growth. Moreover, while overexpression of both cyclin E and A can promote resistance to the CDK4/6i and CDK2i combination, cyclin E plays a more pivotal role in developing resistance. These findings highlight the potential of sustained CDK4/6i therapy and the incorporation of CDK2i to mitigate resistance in HR+ breast cancer.
2024-10-10 | GSE279160 | GEO
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:TNBC response to CDK4/6 inhibitors plus RANKL inhibitors
| PRJNA1162906 | ENA
Project description:The combination of endocrine therapy (ET) with CDK4/6 inhibitors (CDK4/6i) was the most recent life-changing hallmark in metastatic Luminal breast cancer (BC). However, intrinsic and acquired resistance affect long-term efficacy. Here, we studied the role of receptor activator of nuclear factor-kB (RANK) pathway in CDK4/6i resistance. We found that RANK overexpression in Luminal BC associates with intrinsic resistance to CDK4/6i, both in vitro and in mouse xenografts. Transcriptomic analysis of mouse tumors highlighted decreased proliferation rate and chronic interferon (IFN)-response as resistance drivers.
2023-06-09 | GSE224435 | GEO
Project description:Purpose: Breast cancers with ESR1 mutations are resistant to antiestrogen therapy. We aimed to investigate the association of ESR1 mutations with resistance to CDK4/6 inhibitors (CDK4/6i) using real-world data analysis and experimental validation. Patients and Methods: A total of 3,958 patients with estrogen receptor-positive (ER+) metastatic breast cancer with DNA sequencing data were analyzed. Breast tumor DNA and circulating tumor (ct) DNA were sequenced using the Tempus xT tumor assay and Tempus xF liquid biopsy, respectively. Patients were stratified into either treated with CDK4/6i (breast tumors: 1,070; ctDNA: 1,885) or CDK4/6i naïve (breast tumors: 750; ctDNA: 253). Engineered MCF7 cells carrying ESR1 Y537S or D538G knock-in mutations were used to study antitumor efficacy of the CDK4/6i, palbociclib in vitro and in vivo. Results: In both xF and xT assays, ESR1 mutations were the only somatic alterations significantly more frequent in those who received CDK4/6i than those who did not. Knock-in of ESR1 Y537S or ESR1 D538G in MCF7 cells resulted in upregulation of cell cycle-related gene signatures upon treatment with CDK4/6i ± antiestrogen compared to cells with non-mutant ESR1. MCF7 xenografts harboring ESR1 Y537S and D538G mutations established in nude mice were resistant to palbociclib. Conclusions: We report herein real-world and preclinical evidence that ESR1 mutations, particularly Y537S and D538G, can drive resistance to CDK4/6 inhibitors.
2024-11-12 | GSE281302 | GEO
Project description:Neurofibromin/NF1-depletion (NF1low) is associated with endocrine therapy resistance in approximately 20% of ER+/HER2– early-stage breast cancer but specific treatments for NF1low tumors are not established. Proteogenomic analyses on ER+/HER2– breast cancer demonstrated that NF1low tumors exhibit elevated CDK4/6 activity. NF1-silencing in cell lines promoted ER recruitment to CCND1, thus increasing cyclin-D1 levels. Additionally, RAF is demonstrated to directly phosphorylate the CDK4 activation-loop (pT172) thus providing a direct connection between NF1 loss and an increase in CDK4 activity. Consequently, NF1low cancer cells are differentially sensitive to a fulvestrant plus CDK4/6 inhibitor (CDK4/6i) combination, with cell-death induction in vitro, and durable tumor regressions in ER+ NF1low PDX models in vivo. Furthermore, NF1low ER+/HER2– tumors treated neoadjuvantly with 4 weeks of anastrozole exhibited a minimal reduction of a multigene mRNA proliferation score vs NF1high tumors but exhibited marked sensitivity to the subsequent addition of palbociclib. In conclusion, dual ER and downstream RAF activation following NF1-loss drives endocrine therapy resistance and CDK4/6i sensitivity in NF1low ER+ breast cancer. NF1 status should therefore be prioritized for biomarker investigations in adjuvant CDK4/6i trials to determine whether the NF1low status identifies a particularly sensitive subset where CDK4/6i therapy is critical.
2025-05-27 | GSE273881 | GEO
Project description:Selective inhibitors that target cyclin dependent kinases 4 and 6 (CDK4/6i) are FDA approved for treatment of a subset of breast cancers and are being evaluated in numerous clinical trials for other cancers. Despite this advance, a subset of tumors are intrinsically resistant to these drugs and acquired resistance is nearly inevitable. Recent mechanistic evidence suggests that in addition to stalling the cell cycle, the anti-tumor effects of CDK4/6i involve the induction of chromosomal instability (CIN). Here, we exploit this mechanism by combining CDK4/6i with other instability-promoting agents to induce maladaptive CIN and irreversible cell fates. Specifically, dual targeting of CDK4/6 and the mitotic kinase NEK2 in vitro drives the accumulation of CIN that induces catastrophic mitoses, cell cycle exit, and cell death. Dual targeting also induces CIN in vivo and significantly decreases mouse tumor volume to a greater extent than either drug alone, without inducing toxicity. Importantly, we provide evidence that breast cancer cells are selectively dependent on NEK2, but non-transformed cells are not, in contrast with other mitotic kinases that are commonly essential in all cell types. These findings implicate NEK2 as a potential therapeutic target for breast cancer that could circumvent the dose-limiting toxicities that are commonly observed when blocking other mitotic kinases. Moreover, these data suggest that NEK2 inhibitors could be used to sensitize tumors to FDA-approved CDK4/6i for the treatment of breast cancers, improving their efficacy and providing a foundation for expanding the patient population that could benefit from CDK4/6i.
2025-03-05 | GSE277102 | GEO