Short and long-term effects of CDK4/6 inhibition on early stage breast cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA541931 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9029860_1.fastq.gz | Fastqsanger.gz | |||
| SRR9029860_2.fastq.gz | Fastqsanger.gz | |||
| SRR9029870_1.fastq.gz | Fastqsanger.gz | |||
| SRR9029870_2.fastq.gz | Fastqsanger.gz | |||
| SRR9029861_1.fastq.gz | Fastqsanger.gz |
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Project description:CDK4/6 inhibitors are used in the treatment of advanced estrogen receptor (ER)(+) breast cancer (BC). Their efficacy in ER(-) and early stage BC is currently under investigation. Here, we show that palbociclib, a CDK4/6 inhibitor, can inhibit both progression of ductal carcinoma in situ (DCIS) and growth of invasive disease in both an ER(-) basal BC model (MCFDCIS) and an ER(+) luminal model (MCF7 intraductal injection). In MCFDCIS cells palbociclib repressed cell cycle gene expression, inhibited proliferation, induced senescence and normalized tumorspheres formed in Matrigel whilst the formation of acini by normal mammary epithelial cells (MCF10A) was not affected. Palbociclib treatment of mice with MCFDCIS tumors inhibited their malignant progression and reduced proliferation of invasive lesions. Transcriptomic analysis of the tumor and stromal cell compartments showed that cell cycle and senescence genes, and MUC16, an ovarian cancer biomarker gene, were repressed during treatment. Knockdown of MUC16 in MCFDCIS cells inhibited proliferation of invasive lesions but not progression of DCIS. After cessation of palbociclib treatment genes associated with differentiation, e.g. p63, inflammation, IFNγ response and antigen processing and presentation remained suppressed in the tumor and surrounding stroma. We conclude that palbociclib can prevent progression of DCIS and is anti-proliferative in ER(-) invasive disease mediated in part via MUC16. Lasting effects of CDK4/6 inhibition after drug withdrawal on differentiation and the immune response could impact the approach to treatment of early stage ER(-) breast cancer.
2019-08-30 | GSE130903 | GEO
Project description:Small molecule inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, while their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunological T cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous anti-tumor T cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor (CAR)-T cells, and induced an RB-dependent T cell phenotype supportive of favorable responses to immune checkpoint blockade in melanoma patients. Taken together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost anti-tumor T cell immunity.
2021-08-25 | GSE182659 | GEO
Project description:Small molecule inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, while their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunological T cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous anti-tumor T cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor (CAR)-T cells, and induced an RB-dependent T cell phenotype supportive of favorable responses to immune checkpoint blockade in melanoma patients. Taken together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost anti-tumor T cell immunity.
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Project description:Small molecule inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, while their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunological T cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous anti-tumor T cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor (CAR)-T cells, and induced an RB-dependent T cell phenotype supportive of favorable responses to immune checkpoint blockade in melanoma patients. Taken together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost anti-tumor T cell immunity.
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Project description:Small molecule inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, while their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunological T cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous anti-tumor T cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor (CAR)-T cells, and induced an RB-dependent T cell phenotype supportive of favorable responses to immune checkpoint blockade in melanoma patients. Taken together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost anti-tumor T cell immunity.
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Project description:Small molecule inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, while their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunological T cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous anti-tumor T cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor (CAR)-T cells, and induced an RB-dependent T cell phenotype supportive of favorable responses to immune checkpoint blockade in melanoma patients. Taken together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost anti-tumor T cell immunity.
2021-08-25 | GSE182652 | GEO
Project description:Small molecule inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, while their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunological T cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous anti-tumor T cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor (CAR)-T cells, and induced an RB-dependent T cell phenotype supportive of favorable responses to immune checkpoint blockade in melanoma patients. Taken together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost anti-tumor T cell immunity.
2021-08-25 | GSE182650 | GEO
Project description:Small molecule inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, while their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunological T cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous anti-tumor T cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor (CAR)-T cells, and induced an RB-dependent T cell phenotype supportive of favorable responses to immune checkpoint blockade in melanoma patients. Taken together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost anti-tumor T cell immunity.
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Project description:Small molecule inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, while their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunological T cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous anti-tumor T cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor (CAR)-T cells, and induced an RB-dependent T cell phenotype supportive of favorable responses to immune checkpoint blockade in melanoma patients. Taken together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost anti-tumor T cell immunity.
2021-08-25 | GSE182655 | GEO
Project description:Small molecule inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, while their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunological T cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous anti-tumor T cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor (CAR)-T cells, and induced an RB-dependent T cell phenotype supportive of favorable responses to immune checkpoint blockade in melanoma patients. Taken together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost anti-tumor T cell immunity.
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