PI3 kinase/mTOR inhibition increases sensitivity of ER positive breast cancers to CDK4/6 inhibition by blocking cell cycle re-entry driven by cyclinD1 and inducing apoptosis

Herrera-Abreu, María Teresa; Asghar, Uzma; Elliot, Richard; Pearson, Alex; Nannini, Michelle; Young, Anjuli; Sampath, D.; Dowsett, Mitch; Martin, Lesley Ann; Turner, Nicholas C.

doi:10.1093/annonc/mdv120.01

Cited by 8 publications

(5 citation statements)

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“…However, clinical results of single-agent PI3K inhibitors have been modest to date [83]. Preclinical studies showed that PI3K/Akt/mTOR inhibitors sensitized ER-positive cell lines to CDK4/6 inhibition, and the triple combination with ET, was more effective than double combinations [84]. At the same time, the combination of ribociclib plus the α-specific PI3K inhibitor, alpelisib (BYL719), demonstrated synergistic activity in PIK3CA mutant BC cell lines.…”

Section: Biological Rationale For Novel Combination Strategiesmentioning

confidence: 99%

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

Piezzo

Cocco

Caputo

et al. 2020

IJMS

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Deregulation of cell cycle, via cyclin D/CDK/pRb pathway, is frequently observed in breast cancer lending support to the development of drugs targeting the cell cycle control machinery, like the inhibitors of the cycline-dependent kinases (CDK) 4 and 6. Up to now, three CDK4/6 inhibitors have been approved by FDA for the treatment of hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. These agents have been effective in improving the clinical outcomes, but the development of intrinsic or acquired resistance can limit the efficacy of these treatments. Clinical and translational research is now focused on investigation of the mechanism of sensitivity/resistance to CDK4/6 inhibition and novel therapeutic strategies aimed to improve clinical outcomes. This review summarizes the available knowledge regarding CDK4/6 inhibitor, the discovery of new biomarkers of response, and the biological rationale for new combination strategies of treatment.

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Section: Biological Rationale For Novel Combination Strategiesmentioning

confidence: 99%

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

Piezzo

Cocco

Caputo

et al. 2020

IJMS

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“…Loss of Rb is a marker of resistance to treatment, but the majority of HR+ BCs are Rb proficient. 11 Acquired pharmacological resistance to palbociclib occurs via loss of Rb and amplification of cyclin E1, 68 and the combination of a CDK4/6 inhibitor and a CDK2 inhibitor may represent a strategy to overcome resistance to CDK4/6 inhibitors.…”

Section: Hr+/her2− Advanced Bc Unmet Needsmentioning

confidence: 99%

Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2– advanced breast cancer

Corona¹,

Generali²

2018

DDDT

106

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Although early breast cancer (BC) is highly curable, advanced or metastatic disease poses numerous challenges in terms of medical management and treatment decisions and is associated with significantly worse prognosis. Among the new targeted agents, anticancer drugs exploiting the cell-cycle machinery have shown great potential in preclinical studies. CDK4/6 inhibitors target the cyclin D/CDK/retinoblastoma signaling pathway, inducing cell-cycle arrest, reduced cell viability and tumor shrinking. As the cyclin D/CDK complex is activated downstream of estrogen signaling, the combination of CDK4/6 inhibitors with standard endocrine therapies represents a rational approach to elicit synergic antitumor activity in hormone receptor-positive BC. The results of clinical trials have indeed confirmed the superiority of the combination of CDK4/6 inhibitors plus endocrine therapies over endocrine therapy alone. Currently approved are three compounds that exhibit similar structural characteristics as well as biological and clinical activities. Abemaciclib is the latest CDK4/6 inhibitor approved by the US Food and Drug Administration (FDA) in view of the results of the MONARCH 1 and 2 trials. Further trials are ongoing as other important questions await response. In this review, we focus on abemaciclib to examine preclinical and clinical results, describing current therapeutic indications, open questions and ongoing clinical trials.

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“…Finally, the role of novel agents that can potentiate mTOR blockade, is under investigation. The combination of PI3K and CDK4/6 inhibitors demonstrated promising data on apoptosis induction, due to sensitization of ER-positive cells to CDK4/6 inhibition by suppressing cyclin D1 expression [ 25 ]. Targeting the PI3K pathway, such as by dual inhibitors of PI3K and mTOR, is another strategy presently under investigation [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

mTOR inhibitors, a new era for metastatic luminal HER2-negative breast cancer? A systematic review and a meta-analysis of randomized trials

et al. 2016

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We evaluated if standard hormonal therapy (HT) could be improved by the addition of mammalian target of rapamycin inhibitors (mTOR-I) in metastatic luminal breast cancer. A meta-analysis on 4 phase II-III randomized clinical trials was performed. Pooled hazard ratio (HR) for progression free survival (PFS)/ time to progression (TTP) was 0.62 in favor of mTOR-I+HT arm (95% confidence interval [CI] 0.55-0.70; p<0.0001). There was significant heterogeneity for PFS/TTP (Cochran's Q 32, p<0.0001, I2 index 90.6%). Pooled HR for overall survival (OS) was 0.84 in favor of the combination arm (95% CI 0.71-0.99; p=0.04). Heterogeneity was not significant (Cochran's Q 4.47, p=0.1, I2 index 55.3%). Pooled risk ratio (RR) for objective response rate (ORR) was 0.88 in favor of experimental arm (95% CI 0.85-0.91; p<0.0001). Heterogeneity was not significant (Cochran's Q 2.11, p=0.3, I2 index 5.2%). Adverse events (AEs), in particular those of grade 3-4, mostly occurred in mTOR-I+HT arm. Combination therapy of HT plus mTOR-I improves the outcome of metastatic luminal breast cancer patients. Our results provide evidence of a class-effect of these targeting molecules.

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PI3 kinase/mTOR inhibition increases sensitivity of ER positive breast cancers to CDK4/6 inhibition by blocking cell cycle re-entry driven by cyclinD1 and inducing apoptosis

Cited by 8 publications

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Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2– advanced breast cancer

mTOR inhibitors, a new era for metastatic luminal HER2-negative breast cancer? A systematic review and a meta-analysis of randomized trials

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PI3 kinase/mTOR inhibition increases sensitivity of ER positive breast cancers to CDK4/6 inhibition by blocking cell cycle re-entry driven by cyclinD1 and inducing apoptosis

Cited by 8 publications

References 0 publications

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2&ndash; advanced breast cancer

mTOR inhibitors, a new era for metastatic luminal HER2-negative breast cancer? A systematic review and a meta-analysis of randomized trials

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Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2– advanced breast cancer