AKT Inhibitors: New Weapons in the Fight Against Breast Cancer?

Martorana, Federica; Motta, Gianmarco; Pavone, Giuliana; Motta, Lucia; Stella, Stefania; Vitale, Silvia Rita; Manzella, Livia; Vigneri, Paolo

doi:10.3389/fphar.2021.662232

Cited by 143 publications

(121 citation statements)

References 96 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…Intense work over the past few decades has resulted in the development of inhibitors that target ATP-binding sites and/or allosteric sites in multiple kinases, including AURKA and AKT [ 6 , 26 , 193 ]. More recent advances have enabled the development of agents that interfere with binding of kinases to scaffold proteins that support kinase activation [ 11 , 13 , 24 , 194 , 195 , 196 ].…”

Section: Future Directionsmentioning

confidence: 99%

“…Thus, both catalytic and noncatalytic activities play a role in AKT function [ 6 , 21 ] and, similar to AURKA, AKT dysregulation plays a role in many major disorders, including cardiovascular and metabolic diseases and cancer. Taken together, these observations suggest that therapeutic approaches that specifically target kinase catalytic and noncatalytic functions in a context-dependent manner could not only improve efficacy but also minimize potential adverse effects [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Aurora A and AKT Kinase Signaling Associated with Primary Cilia

Nishimura

Yamakawa

Shiromizu

et al. 2021

Cells

View full text Add to dashboard Cite

Dysregulation of kinase signaling is associated with various pathological conditions, including cancer, inflammation, and autoimmunity; consequently, the kinases involved have become major therapeutic targets. While kinase signaling pathways play crucial roles in multiple cellular processes, the precise manner in which their dysregulation contributes to disease is dependent on the context; for example, the cell/tissue type or subcellular localization of the kinase or substrate. Thus, context-selective targeting of dysregulated kinases may serve to increase the therapeutic specificity while reducing off-target adverse effects. Primary cilia are antenna-like structures that extend from the plasma membrane and function by detecting extracellular cues and transducing signals into the cell. Cilia formation and signaling are dynamically regulated through context-dependent mechanisms; as such, dysregulation of primary cilia contributes to disease in a variety of ways. Here, we review the involvement of primary cilia-associated signaling through aurora A and AKT kinases with respect to cancer, obesity, and other ciliopathies.

show abstract

Section: Future Directionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aurora A and AKT Kinase Signaling Associated with Primary Cilia

Nishimura

Yamakawa

Shiromizu

et al. 2021

Cells

View full text Add to dashboard Cite

show abstract

“…The identification of biomarkers of response and resistance to targeted therapies is of pivotal importance in the era of personalized medicine [ 46 , 47 ].…”

Section: Biomarkers Of Responsementioning

confidence: 99%

A New Kid on the Block: Sacituzumab Govitecan for the Treatment of Breast Cancer and Other Solid Tumors

et al. 2021

Self Cite

View full text Add to dashboard Cite

Human trophoblast cell-surface antigen-2 (Trop-2) is a membrane glycoprotein involved in cell proliferation and motility, frequently overexpressed in epithelial tumors. Thus, it represents an attractive target for anticancer therapies. Sacituzumab govitecan (SG) is a third-generation antibody-drug conjugate, consisting of an anti-Trop-2 monoclonal antibody (hRS7), a hydrolyzable linker, and a cytotoxin (SN38), which inhibits topoisomerase 1. Specific pharmacological features, such as the high antibody to payload ratio, the ultra-toxic nature of SN38, and the capacity to kill surrounding tumor cells (the bystander effect), make SG a very promising drug for cancer treatment. Indeed, unprecedented results have been observed with SG in patients with heavily pretreated advanced triple-negative breast cancer and urothelial carcinomas, and the drug has already received approval for these indications. These results are coupled with a manageable toxicity profile, with neutropenia and diarrhea as the most frequent adverse events, mainly of grades 1–2. While several trials are exploring SG activity in different tumor types and settings, potential biomarkers of response are under investigation. Among these, Trop-2 overexpression and the presence of BRCA1/2 mutations seem to be the most promising. We review the available literature concerning SG, with a focus on its toxicity spectrum and possible biomarkers of its response.

show abstract

“…Recent clinical trials have led to the clinical approval of the mTOR inhibitor everolimus in conjunction with exemestane as well as the PI3K inhibitor, alpelisib, in combination with fulvestrant for the treatment of patients with advanced or metastatic ER+, PR+, HER2-negative, PIK3CA mutant tumors [ 199 , 200 , 201 ]. In addition, the combination of fulvestrant with the AKT inhibitor capivasertib is in clinical trials [ 202 , 203 , 204 ]. Beyond PI3K/Akt family inhibitors, CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib have been approved in conjunction with hormone therapy for treatment of HR+/HER2- treatment naïve or hormone therapy treated metastatic breast cancer patients [ 205 , 206 ].…”

Section: Metabolism In Therapeutic Resistance and Novel Clinical Opportunitiesmentioning

confidence: 99%

Nuclear Receptor-Mediated Metabolic Reprogramming and the Impact on HR+ Breast Cancer

Hussein

Khanna

Yunus

et al. 2021

Cancers

View full text Add to dashboard Cite

Metabolic reprogramming enables cancer cells to adapt to the changing microenvironment in order to maintain metabolic energy and to provide the necessary biological macromolecules required for cell growth and tumor progression. While changes in tumor metabolism have been long recognized as a hallmark of cancer, recent advances have begun to delineate the mechanisms that modulate metabolic pathways and the consequence of altered signaling on tumorigenesis. This is particularly evident in hormone receptor positive (HR+) breast cancers which account for approximately 70% of breast cancer cases. Emerging evidence indicates that HR+ breast tumors are dependent on multiple metabolic processes for tumor progression, metastasis, and therapeutic resistance and that changes in metabolic programs are driven, in part, by a number of key nuclear receptors including hormone-dependent signaling. In this review, we discuss the mechanisms and impact of hormone receptor mediated metabolic reprogramming on HR+ breast cancer genesis and progression as well as the therapeutic implications of these metabolic processes in this disease.

show abstract

AKT Inhibitors: New Weapons in the Fight Against Breast Cancer?

Cited by 143 publications

References 96 publications

Aurora A and AKT Kinase Signaling Associated with Primary Cilia

Aurora A and AKT Kinase Signaling Associated with Primary Cilia

A New Kid on the Block: Sacituzumab Govitecan for the Treatment of Breast Cancer and Other Solid Tumors

Nuclear Receptor-Mediated Metabolic Reprogramming and the Impact on HR+ Breast Cancer

Contact Info

Product

Resources

About