Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer

Ge, Jennifer Y; Shu, Shaokun; Kwon, Mijung; Jovanović, Bojana; Murphy, Katherine; Gulvady, Anushree C.; Fassl, Anne; Trinh, Anne; Kuang, Yanan; Heavey, Grace A.; Luoma, Adrienne; Paweletz, Cloud P.; Thorner, Aaron R.; Wucherpfennig, Kai W.; Qi, Jun; Brown, Myles; Siciński, Piotr; McDonald, Thomas O.; Pellman, David; Michor, Franziska; Polyák, Kornélia

doi:10.1038/s41467-020-16170-3

Cited by 48 publications

(36 citation statements)

References 63 publications

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“…Collectively, these data demonstrate that polyploidy associated with TIS escape may play a central role in the survival of some cancer cells through the acquisition of a mesenchymal phenotype. This will lead to eventual clonogenic re-growth of a tumor following genotoxic stress induced by radio- or chemotherapy [ 76 , 87 , 151 , 152 , 161 , 162 , 163 , 164 , 165 ].…”

Section: Senescence Escape Is a Driver Of Tumor Resiliencementioning

confidence: 99%

Cellular Plasticity: A Route to Senescence Exit and Tumorigenesis

Blander

Morel

Senaratne

et al. 2021

Cancers

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Senescence is a dynamic, multistep program that results in permanent cell cycle arrest and is triggered by developmental or environmental, oncogenic or therapy-induced stress signals. Senescence is considered as a tumor suppressor mechanism that prevents the risk of neoplastic transformation by restricting the proliferation of damaged cells. Cells undergoing senescence sustain important morphological changes, chromatin remodeling and metabolic reprogramming, and secrete pro-inflammatory factors termed senescence-associated secretory phenotype (SASP). SASP activation is required for the clearance of senescent cells by innate immunity. Therefore, escape from senescence and the associated immune editing would be a prerequisite for tumor initiation and progression as well as therapeutic resistance. One of the possible mechanisms for overcoming senescence could be the acquisition of cellular plasticity resulting from the accumulation of genomic alterations and genetic and epigenetic reprogramming. The modified composition of the SASP produced by these reprogrammed cancer cells would create a permissive environment, allowing their immune evasion. Additionally, the SASP produced by cancer cells could enhance the cellular plasticity of neighboring cells, thus hindering their recognition by the immune system. Here, we propose a comprehensive review of the literature, highlighting the role of cellular plasticity in the pro-tumoral activity of senescence in normal cells and in the cancer context.

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Section: Senescence Escape Is a Driver Of Tumor Resiliencementioning

confidence: 99%

Cellular Plasticity: A Route to Senescence Exit and Tumorigenesis

Blander

Morel

Senaratne

et al. 2021

Cancers

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“…These multiple functions suggested the critical roles of circRNAs during tumorigenesis and progression in TNBCs. Combination therapy was the most reliable for cancer therapy in TNBCs [ 23 , 24 ]. Generally, different reagents target different molecules in the same pathway to avoid drug resistance.…”

Section: Discussionmentioning

confidence: 99%

CircCD44 plays oncogenic roles in triple-negative breast cancer by modulating the miR-502–5p/KRAS and IGF2BP2/Myc axes

Gao

Zhang

et al. 2021

Mol Cancer

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Background Emerging studies have revealed the potent functions of circRNAs in breast cancer tumorigenesis. However, the biogenesis, biofunction and mechanism of circRNAs in triple-negative breast cancer (TNBC) are largely unknown. Methods High-throughput RNA sequencing was applied to identify dysregulated circRNAs in TNBCs and paired normal tissues. RNA pulldown and luciferase assays were performed to investigate the interaction between circular CD44 (circCD44, also annotated as hsa_circ_0021735) and miR-502–5p. RNA pulldown and RIP assays were used to investigate the interaction between circCD44 and IGF2BP2. Cell viability, colony formation, migration/invasion assays and in vivo tumorigenesis were used to investigate circCD44 biological functions. Results CircCD44 is an uncharacterized circRNA, which is highly expressed in TNBC, and its expression is negatively correlated with the prognosis of TNBC patients. CircCD44 promotes TNBC proliferation, migration, invasion and tumorigenesis at least partially by sponging miR-502–5p and interacting with IGF2BP2. Conclusion Our data suggested that overexpressed circCD44 promotes TNBC progression. CircCD44 is potentially a novel diagnostic and therapeutic marker for TNBC patients.

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“…Single cell analyses and cellular barcode-mediated lineage tracing revealed that the fulvestrant-resistant phenotype pre-existed in a low-abundance genomic subclone prior to treatment of cell lines ( 106 ). Furthermore, cell line-based studies of resistance to experimental epigenetic-targeted therapies such as BET bromodomain inhibitors have revealed potential synergistic drug combinations that may prove useful clinically in the future ( 107 , 108 ).…”

Section: In Vitro Models Of Therapy Resistance—2dmentioning

confidence: 99%

Laboratory Models for Investigating Breast Cancer Therapy Resistance and Metastasis

Roarty

Echeverria

2021

Front. Oncol.

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While numerous therapies are highly efficacious in early-stage breast cancers and in particular subsets of breast cancers, therapeutic resistance and metastasis unfortunately arise in many patients. In many cases, tumors that are resistant to standard of care therapies, as well as tumors that have metastasized, are treatable but incurable with existing clinical strategies. Both therapy resistance and metastasis are multi-step processes during which tumor cells must overcome diverse environmental and selective hurdles. Mechanisms by which tumor cells achieve this are numerous and include acquisition of invasive and migratory capabilities, cell-intrinsic genetic and/or epigenetic adaptations, clonal selection, immune evasion, interactions with stromal cells, entering a state of dormancy or senescence, and maintaining self-renewal capacity. To overcome therapy resistance and metastasis in breast cancer, the ability to effectively model each of these mechanisms in the laboratory is essential. Herein we review historic and the current state-of-the-art laboratory model systems and experimental approaches used to investigate breast cancer metastasis and resistance to standard of care therapeutics. While each model system has inherent limitations, they have provided invaluable insights, many of which have translated into regimens undergoing clinical evaluation. We will discuss the limitations and advantages of a variety of model systems that have been used to investigate breast cancer metastasis and therapy resistance and outline potential strategies to improve experimental modeling to further our knowledge of these processes, which will be crucial for the continued development of effective breast cancer treatments.

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Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer

Cited by 48 publications

References 63 publications

Cellular Plasticity: A Route to Senescence Exit and Tumorigenesis

Cellular Plasticity: A Route to Senescence Exit and Tumorigenesis

CircCD44 plays oncogenic roles in triple-negative breast cancer by modulating the miR-502–5p/KRAS and IGF2BP2/Myc axes

Laboratory Models for Investigating Breast Cancer Therapy Resistance and Metastasis

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