Microarray gene expression data from MPFR cells treated with inhibitors of the PI3K/AKT/mTOR pathway
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE262611 | GEO | 2025/12/18
REPOSITORIES: GEO
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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: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.
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Project description:Resistance to aromatase inhibitor (AI) treatment and combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) are crucial clinical challenges in treating estrogen receptor-positive (ER+) breast cancer. Understanding the resistance mechanisms and identifying reliable predictive biomarkers and novel treatment combinations to overcome resistance are urgently needed. Herein, we show that upregulation of CDK6, p-CDK2, and/or cyclin E1 is associated with adaptation and resistance to AI-monotherapy and combined CDK4/6i and ET in ER+ advanced breast cancer. Importantly, co-targeting CDK2 and CDK4/6 with ET synergistically impairs cellular growth, induces cell cycle arrest and apoptosis, and delays progression in AI-resistant and combined CDK4/6i and fulvestrant-resistant cell models and in an AI-resistant autocrine breast tumor in a postmenopausal xenograft model. Analysis of CDK6, p-CDK2, and/or cyclin E1 expression as a combined biomarker in metastatic lesions of ER+ advanced breast cancer patients treated with AI-monotherapy or combined CDK4/6i and ET revealed a correlation between high biomarker expression and shorter progression-free survival (PFS), and the biomarker combination was an independent prognostic factor in both patients cohorts. Our study supports the clinical development of therapeutic strategies co-targeting ER, CDK4/6 and CDK2 following progression on AI-monotherapy or combined CDK4/6i and ET to improve survival of patients exhibiting high tumor levels of CDK6, p-CDK2, and/or cyclin E1.
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Project description:RET is overexpressed in breast cancer cell lines resistant to combined CDK4/6i and endocrine therapy. siRNA-mediated knockdown of RET was performed to identify main pathways altered upon RET-knockdown. We used microarrays to detail the global programme of gene expression following RET knockdown in 2 cell models resistant to combined CDK4/6 inhibitor palbociclib and fulvestrant (MPFR and TPFR). MPFR-ret and TPFR-ret were compared to MPFR-ctrl and TPFR-ctrl, respectively. The gene expression analysis revealed a significant number of genes altered in the knockdown (ret) vs. ctrl
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Project description:Resistance to CDK4/6 inhibitors plus endocrine therapy, standard of care for HR+/HER2-neg metastatic breast cancer (MBC) patients, remains as a clinical problem with limited therapeutic options after disease progression. Treatment with abemaciclib after progression on a prior CDK4/6i has received increasing interest. However, molecular predictors of cross-resistance and unique mechanism of resistance to each CDK4/6i are unknown. In this study, multiomics analyses revealed ≥30 differentially altered pathways between palbociclib and abemaciclib resistant models. Mechanistic, preclinical and retrospective clinical evidence showed that HR+/HER2-neg MBC tumors refractory to palbociclib still may be responsive to abemaciclib. Based on the unique mechanisms of resistance to each CDK4/6i, we propose that patients who would benefit from abemaciclib treatment post progression on palbociclib could be selected based on the Hallmark gene set enrichment of G2/M pathway, while those who most probably would be refractory could be identified base on the gene set enrichment of OXPHOS pathway.
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Project description:Resistance to CDK4/6 inhibitors plus endocrine therapy, standard of care for HR+/HER2-neg metastatic breast cancer (MBC) patients, remains as a clinical problem with limited therapeutic options after disease progression. Treatment with abemaciclib after progression on a prior CDK4/6i has received increasing interest. However, molecular predictors of cross-resistance and unique mechanism of resistance to each CDK4/6i are unknown. In this study, multiomics analyses revealed ≥30 differentially altered pathways between palbociclib and abemaciclib resistant models. Mechanistic, preclinical and retrospective clinical evidence showed that HR+/HER2-neg MBC tumors refractory to palbociclib still may be responsive to abemaciclib. Based on the unique mechanisms of resistance to each CDK4/6i, we propose that patients who would benefit from abemaciclib treatment post progression on palbociclib could be selected based on the Hallmark gene set enrichment of G2/M pathway, while those who most probably would be refractory could be identified base on the gene set enrichment of OXPHOS pathway.
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Project description:Cyclin-dependent kinases 4 and 6 (CDK4/6) are essential drivers of the cell cycle and are also critical for the initiation and progression of diverse malignancies. Pharmacological inhibitors targeting CDK4/6 have demonstrated significant activity against various tumor types such as breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i) (such as palbociclib) remain an immense obstacle in clinical and the underlying mechanisms have not been fully understood. Using Conditional medium co-culture, quantitative high-throughput combinational screen (qHTCS), and genomic sequencing, we report that the RUNX1-PDGFBB-AKt pathway was significantly elevated in palbociclib-resistance cells. Inhibition of this axis can enhance the therapeutic efficacy of Palbociclib and surmount Palbociclib resistance both in vitro and in vivo. Mechanistically, we found that O-GlcNAc transferase (OGT) modifies RUNX1 with O-GlcNAcylation at Serine 252 (Ser252), thereby stabilizing RUNX1 protein expression, which is crucial in regulating PDGFBB expression. Significantly, clinical studies also confirm that RUNX1-PDGFBB-Akt pahtway was elevated in palbociclib-resistance patients. Collectively, these results reveal a previously unrecognized mechanism by which RUNX1-PDGFBB mediated palbociclib resistance, and provide valuable insights for the development of innovative therapeutic strategies in future clinical contexts.
2025-01-30 | GSE264264 | 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:Endocrine therapies (ET) combined with CDK4/6 inhibition (CDK4/6i) is standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however lethal drug resistance is common. Proteogenomic analyses of 22 ER+ breast cancer patient-derived xenografts (PDXs) demonstrated that PKMYT1, a WEE1 homolog, is highly estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2 independent. In clinical samples, high PKMYT1 mRNA is a resistance biomarker for both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib(RP-6306) and gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53 in vitro; the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX organoids and xenografts, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. These results demonstrate the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6i resistant TP53 mutant ER+ breast cancer.
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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.
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