The CDK4/6 inhibitor revolution — a game-changing era for breast cancer treatment

Morrison, Laura; Loibl, Sibylle; Turner, Nicholas C.

doi:10.1038/s41571-023-00840-4

Cited by 66 publications

(15 citation statements)

References 187 publications

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“…Notably, the clinical approval of inhibitors targeting CDK4/6, whose activity is determined by cyclin D1 protein level, highlights the pronounced clinical significance of cyclin D1 in the context of cancer therapeutics, particularly for breast cancer. 53 Unlike the strong apoptosis (determined by cleaved caspase 3 [cCasp3]) observed in PC9, no clear apoptosis was observed following CCR6 inhibition in PC9GR ( Figures 4 G and 4H). These data suggest that the substantial decrease in cell growth observed with the combined treatment of erlotinib and iCCR6 ( Figures 4 C and 4D) is primarily attributed to the suppression of cyclin D1 through the inhibition of ERK1/2 activity ( Figure 4 H).…”

Section: Resultsmentioning

confidence: 94%

Systematic omics analysis identifies CCR6 as a therapeutic target to overcome cancer resistance to EGFR inhibitors

Kwon,

Cha,

Lee

2024

iScience

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Section: Resultsmentioning

confidence: 94%

Systematic omics analysis identifies CCR6 as a therapeutic target to overcome cancer resistance to EGFR inhibitors

Kwon,

Cha,

Lee

2024

iScience

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“…Although CDK4/6 inhibitors in the metastatic setting have demonstrated significant clinical benefit in ER+/HER2- patients, results from PALLAS, PENELOPE-B, monarchE and NATALEE trials, where the benefit of CDK4/6 inhibition was tested in the adjuvant setting in early-stage ER+/HER2- patients remain conflicting [22], [23], [24], [25], [26]. There is consensus within the cancer research community that the adjuvant use of CDK4/6 inhibitors, which would greatly benefit a subset of patients, is only achievable with the identification of predictive biomarkers that can be assessed at diagnosis [27], [28], [29], [30].…”

Section: Discussionmentioning

confidence: 99%

“…To identify the mechanism by which the G55V mutation confers resistance to endocrine treatment, we conducted RNAseq analysis of G55V-and WT-bearing isogenic MCF7 cells at baseline and after fulvestrant treatment. A reactome pathway analysis identified cell cycle dysregulation as one of the pathways distinguishing the G55V-bearing cellular response to fulvestrant from that of WT- Although CDK4/6 inhibitors in the metastatic setting have demonstrated significant clinical benefit in ER+/HER2-patients, results from PALLAS, PENELOPE-B, monarchE and NATALEE trials, where the benefit of CDK4/6 inhibition was tested in the adjuvant setting in early-stage ER+/HER2-patients remain conflicting [22], [23], [24], [25], [26]. There is consensus within the cancer research community that the adjuvant use of CDK4/6 inhibitors, which would greatly benefit a subset of patients, is only achievable with the identification of predictive biomarkers that can be assessed at diagnosis [27], [28], [29], [30].…”

Section: Mlh1 Mutations Cause Varying Degrees Of Endocrine Treatment ...mentioning

confidence: 99%

Aberrant cytoplasmic localization of MLH1 characterizes a sub-clonal breast cancer cell population that seeds recurrence

Mazumder,

DeWitt,

Oropeza

et al. 2024

Preprint

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Mismatch repair loss is a commonly used prognostic and predictive clinical diagnostic across several cancer types. Currently, mismatch repair loss is assessed using bulk tumor approaches to assess genome instability (e.g. tumor mutation burden, microsatellite instability) or by immunohistochemistry for total protein level of individual mismatch repair proteins. Here, we identify a novel mechanism by which mismatch repair proteins are dysregulated that cannot be detected by either of these clinical diagnostic approaches. Sub-clonal mutations in MLH1, a principal mismatch repair gene, detected in tumors from estrogen receptor positive breast cancer patients do not impact abundance of MLH1 protein, nor do they contribute sufficiently to genomic instability to enable detection at the bulk tumor level. However, as we demonstrate here, some of these sub-clonal mutations aberrantly localize MLH1 protein to the cytoplasm, preventing MLH1-mediated activation of the G1 cell cycle checkpoint in response to standard targeted endocrine therapies. The lack of G1 checkpoint activity results in treatment resistance of a sub-clonal persister-like population that remains viable even after long-term exposure to treatment. The dependence on G1 progression, however, renders these sub-clonal populations acutely sensitive to CDK4/6 inhibitors such as palbociclib. Overall, data presented here strongly suggests that aberrant cytoplasmic localization of MLH1 can serve as a predictive biomarker to more accurately predict resistance to endocrine therapy, and sensitivity to combinatorial treatment with CDK4/6 inhibitors. This is particularly important in the adjuvant setting where the risk-benefit ratio for untargeted CDK4/6 inhibitor intervention is narrow. It is possible that these findings have important implications for treatment guidance in other non-breast cancer types as well, where MLH1 mutation is even more frequent.

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“…Cyclin-dependent kinases 4 and 6 are enzymes that mediate transition through the cell cycle and guard genome integrity [ 134 ]. ER-positive breast cancer cells are reliant on CDK4/6 for cell cycle progression [ 135 ]. Inhibition of CDK4/6 in combination with AIs in metastatic HR-positive, HER2-negative breast cancer has been shown to improve progression-free survival and objective response rate compared to AI monotherapy [ 136 , 137 , 138 ].…”

Section: Treatment Of Bone Metastatic Breast Cancermentioning

confidence: 99%

A Representative Clinical Course of Progression, with Molecular Insights, of Hormone Receptor-Positive, HER2-Negative Bone Metastatic Breast Cancer

Magno,

Bussard

2024

IJMS

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Despite treatment advances, breast cancer remains a leading cause of death of women in the United States, mostly due to metastatic disease. Bone is a preferential site for breast cancer metastasis, and most metastatic breast cancer patients experience bone involvement at the time of death. The majority of patients with bone metastatic breast cancer are first diagnosed with and treated for early-stage disease, and from development of early-stage breast cancer to the recurrence of cancer in the bones, up to 30 years may elapse. Throughout this timeframe, a typical patient undergoes many treatments that have effects on the bone microenvironment. Therefore, this review explores the clinical course of a representative patient with hormone receptor-positive bone metastatic breast cancer, examining key treatment options at each stage and their effects on preventing and treating bone metastases.

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The CDK4/6 inhibitor revolution — a game-changing era for breast cancer treatment

Cited by 66 publications

References 187 publications

Systematic omics analysis identifies CCR6 as a therapeutic target to overcome cancer resistance to EGFR inhibitors

Systematic omics analysis identifies CCR6 as a therapeutic target to overcome cancer resistance to EGFR inhibitors

Aberrant cytoplasmic localization of MLH1 characterizes a sub-clonal breast cancer cell population that seeds recurrence

A Representative Clinical Course of Progression, with Molecular Insights, of Hormone Receptor-Positive, HER2-Negative Bone Metastatic Breast Cancer

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