Clinical and Pharmacologic Differences of CDK4/6 Inhibitors in Breast Cancer

George, Mridula; Qureshi, Sadaf; Omene, Coral; Toppmeyer, Deborah; Ganesan, Shridar

doi:10.3389/fonc.2021.693104

Cited by 94 publications

(74 citation statements)

References 84 publications

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“…Despite overlap in on-target hematological toxicities, it is important to note that approved CDK4/6i have reportedly different pharmacological activity and overall toxicity profiles 41 – 43 , which may facilitate treatment choice, particularly in ICI combination regimens. For example, palbociclib and ribociclib have relatively lower off-target toxicities (notably gastrointestinal) than abemaciclib, while the frequency of hepatotoxicity is highest for ribociclib 44 .…”

Section: Boosting Response Rates To Icimentioning

confidence: 99%

Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?

2022

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CDK4/6 inhibitors (CDK4/6i) were developed as a cancer therapeutic on the basis of their tumor-intrinsic cytostatic potential, but have since demonstrated profound activity as immunomodulatory agents. While currently approved to treat hormone receptor-positive breast cancer, these inhibitors are under investigation in clinical trials as treatments for a range of cancer types, including melanoma. Melanoma is a highly immunogenic cancer, and has always been situated at the forefront of cancer immunotherapy development. Recent revelations into the immunotherapeutic activity of CDK4/6i, therefore, have significant implications for the utility of these agents as melanoma therapies. In recent studies, we and others have proven the immunomodulatory effects of CDK4/6i to be multifaceted and complex. Among the most notable effects, CDK4/6 inhibition induces transcriptional reprogramming in both tumor cells and immune cells to enhance tumor cell immunogenicity, promote an immune-rich tumor microenvironment, and skew T cell differentiation into a stem-like phenotype that is more amenable to immune checkpoint inhibition. However, in some contexts, the specific immunomodulatory effects of CDK4/6i may impinge on anti-tumor immunity. For example, CDK4/6 inhibition restricts optimal T cells expansion, and when used in combination with BRAF/MEK-targeted therapies, depletes immune-potentiating myeloid subsets from the tumor microenvironment. We propose that such effects, both positive and negative, may be mitigated or exacerbated by altering the CDK4/6i dosing regimen. Here, we discuss what the most recent insights mean for clinical trial design, and propose clinical considerations and strategies that may exploit the full immunotherapeutic potential of CDK4/6 inhibitors.

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Section: Boosting Response Rates To Icimentioning

confidence: 99%

Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?

2022

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“…Administration is for 21 days followed by a break of one week for neutrophil count recovery. In comparison, the half-life of abemaciclib is <24 h. It induces relatively less myelosuppression and is dosed twice daily [ 120 ] Palbociclib and ribociclib have minimal GI toxicities compared to abemaciclib, which has extensive GI toxicities [ 121 ]. However, abemaciclib-mediated bone marrow toxicity is less serious than palbociclib and ribociclib-mediated bone marrow toxicities [ 120 ].…”

Section: Inhibition Of Cyclin-dependent Kinases 4/6 (Cdk4/6) As a Sou...mentioning

confidence: 99%

“…In comparison, the half-life of abemaciclib is <24 h. It induces relatively less myelosuppression and is dosed twice daily [ 120 ] Palbociclib and ribociclib have minimal GI toxicities compared to abemaciclib, which has extensive GI toxicities [ 121 ]. However, abemaciclib-mediated bone marrow toxicity is less serious than palbociclib and ribociclib-mediated bone marrow toxicities [ 120 ]. The rate of hematological toxicity, mainly neutropenia, is higher for palbociclib and ribociclib [ 122 ].…”

Section: Inhibition Of Cyclin-dependent Kinases 4/6 (Cdk4/6) As a Sou...mentioning

confidence: 99%

Precision Medicine Highlights Dysregulation of the CDK4/6 Cell Cycle Regulatory Pathway in Pediatric, Adolescents and Young Adult Sarcomas

Barghi

Shannon

Saadatzadeh

et al. 2022

Cancers

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Despite improved therapeutic and clinical outcomes for patients with localized diseases, outcomes for pediatric and AYA sarcoma patients with high-grade or aggressive disease are still relatively poor. With advancements in next generation sequencing (NGS), precision medicine now provides a strategy to improve outcomes in patients with aggressive disease by identifying biomarkers of therapeutic sensitivity or resistance. The integration of NGS into clinical decision making not only increases the accuracy of diagnosis and prognosis, but also has the potential to identify effective and less toxic therapies for pediatric and AYA sarcomas. Genome and transcriptome profiling have detected dysregulation of the CDK4/6 cell cycle regulatory pathway in subpopulations of pediatric and AYA OS, RMS, and EWS. In these patients, the inhibition of CDK4/6 represents a promising precision medicine-guided therapy. There is a critical need, however, to identify novel and promising combination therapies to fight the development of resistance to CDK4/6 inhibition. In this review, we offer rationale and perspective on the promise and challenges of this therapeutic approach.

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“…These combinations have significantly improved clinical outcomes when compared to anti-estrogen monotherapy, as demonstrated by the randomized phase III trials PALOMA, MONALEESA, and MONARCH [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Although these drugs have reported comparable clinical benefits, there are unique differences in their substrate selectivity and pharmacodynamics [ 17 , 18 , 19 ] that could explain the varying differences observed in certain clinical settings. For example, abemaciclib is the only CDKi also approved as a monotherapy in the metastatic setting, and promising data support its use in the adjuvant setting.…”

Section: Introductionmentioning

confidence: 99%

Biological Effects of Cyclin-Dependent Kinase Inhibitors Ribociclib, Palbociclib and Abemaciclib on Breast Cancer Bone Microenvironment

Iuliani

Simonetti

Ribelli

et al. 2022

IJMS

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The CDK4/6 inhibitors (CDKi) palbociclib, ribociclib, and abemaciclib are currently approved in combination with anti-estrogen therapy for the treatment of advanced and/or metastatic hormone receptor-positive/HER2-neu-negative breast cancer patients. Given the high incidence of bone metastases in this population, we investigated and compared the potential effects of palbociclib, ribociclib, and abemaciclib on the breast cancer bone microenvironment. Primary osteoclasts (OCs) and osteoblasts (OBs) were obtained from human monocyte and mesenchymal stem cells, respectively. OC function was evaluated by tartrate-resistant acid phosphatase assay and real-time PCR; OB activity was assessed by an alizarin red assay. OB/breast cancer co-culture models were generated via the seeding of MCF-7 cells on a layer of OBs, and tumor cell proliferation was analyzed using flow cytometry. Here, we showed that ribociclib, palbociclib, and abemaciclib exerted similar inhibitory effects on the OC differentiation and expression of bone resorption markers without affecting OC viability. On the other hand, the three CDKi did not affect the ability of OB to produce bone matrix, even if the higher doses of palbociclib and abemaciclib reduced the OB viability. In OB/MCF-7 co-culture models, palbociclib demonstrated a lower anti-tumor effect than ribociclib and abemaciclib. Overall, our results revealed the direct effects of CDKi on the tumor bone microenvironment, highlighting differences potentially relevant for clinical practice.

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Clinical and Pharmacologic Differences of CDK4/6 Inhibitors in Breast Cancer

Cited by 94 publications

References 84 publications

Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?

Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?

Precision Medicine Highlights Dysregulation of the CDK4/6 Cell Cycle Regulatory Pathway in Pediatric, Adolescents and Young Adult Sarcomas

Biological Effects of Cyclin-Dependent Kinase Inhibitors Ribociclib, Palbociclib and Abemaciclib on Breast Cancer Bone Microenvironment

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