CDK4/6 inhibitors: A potential therapeutic approach for triple negative breast cancer

Saleh, Lubaid; Wilson, Caroline; Holen, Ingunn

doi:10.1002/mco2.97

Cited by 15 publications

(14 citation statements)

References 142 publications

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“…CMGCs and AGC are known to regulate a variety of cell metabolism, growth, proliferation, survival, and anti-apoptosis activities and extensively participate in the control of cell fate decisions; thus, they have been of interest in cancer research. In breast cancer, inhibition of CDK4/6 using small-molecule inhibitors such as palbociclib, abemacilib, and ribociclib has shown substantial promise in early-stage clinical studies, which induce tumor stabilization and increase the rates of tumor shrinkage 56,57 .…”

Section: Discussionmentioning

confidence: 99%

Comprehensive proteome and phosphoproteome analysis reveals the protein characterization of invasive ductal and lobular carcinoma with specific molecular subgroup

Yang

Zuo

et al. 2022

Preprint

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Background Breast cancer is one of the most frequently occurring malignant cancers worldwide. Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the two most common histological subtypes of breast cancer. The prognosis and survival of the two subtypes were significantly different even with specific molecular subgroup. In this study, we aimed to deeply explore molecular characteristics and the relationship between IDC and ILC subtypes in same molecular subgroup of breast cancer using comprehensive proteomics and phosphoproteomics analysis. Methods Cancer tissues and noncancerous adjacent tissues (NATs) with the luminal subtype (ER- and PR-positive, HER2-negative) were obtained from paired IDC and ILC patients respectively. Label-free quantitative proteomics and phosphoproteomics methods were used to detect differentially expressed proteins and the phosphorylation status between 10 paired breast cancer and NATs. Then, bioinformatics analysis was performed to explore the difference between IDC and ILC subtypes, including the difference in protein expression levels and the degree of phosphorylation. Meanwhile, Kinase-Substrate Enrichment Analysis (KSEA) revealed the activation difference of kinases and their substrates between IDC and ILC. Results A total of 5,044 high-confidence proteins and 3,808 phosphoproteins were identified from breast cancer tissues. The protein phosphorylation level in ILC tissues was higher than that in IDC tissues. From the quantitative analysis of 1259 proteins and 560 phosphoproteins with high patient coverage, Histone H1.10, Complement C4-B and Crk-like protein were found to be significantly differentially expressed in the two subtype tissues from the proteomics analysis. Moreover, the differences in protein expression of Septin-2, Septin-9, Heterogeneous nuclear ribonucleoprotein A1 and Kinectin and their phosphorylation clearly distinguished IDC from ILC. In addition, differentially expressed proteins and differentially expressed phosphoproteins in IDC were primarily related to energy metabolism and MAPK pathway, while ILC subtypes were more closely involved in the AMPK and p53/p21 pathways. Furthermore, the kinomes from IDC were primarily significantly activated in the CMGC (Cyclin-dependent kinases, Mitogen-activated protein kinases, Glycogen synthase kinases and CDK-like kinases) groups. Conclusions Our research provides insights into the molecular characterization of IDC and ILC and contributes to discovering novel targets for further drug development and targeted treatment.

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Section: Discussionmentioning

confidence: 99%

Comprehensive proteome and phosphoproteome analysis reveals the protein characterization of invasive ductal and lobular carcinoma with specific molecular subgroup

Yang

Zuo

et al. 2022

Preprint

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“…Currently, there are three FDA‐approved CDK4/6 inhibitors: palbociclib, ribociclib, and abemaciclib which are used in the treatment of ER+/HER2– advanced BC. In TNBC, Rb dysfunction has been evident in approximately 30% of patients, which makes CDK4/6 inhibitors a promising therapeutic option (Hu et al, 2021; Saleh et al, 2021). Several clinical trials are investigating the use of CDK4/6 inhibitors in conjunction with other agents in TNBC.…”

Section: Treatmentmentioning

confidence: 99%

Proteolysis Targeting Chimera (PROTAC) as a promising novel therapeutic modality for the treatment of triple‐negative breast cancer (TNBC)

Dogheim

Amralla²

2023

Drug Development Research

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Breast cancer (BC) is considered one of the most prevalent malignancies impacting women worldwide, constituting 15% of all new cancer cases. It is classified according to its molecular targets into three subtypes; HR+/ERBB2‐, ERBB2+/HR+, or HR‐ and triple‐negative breast cancer (TNBC). TNBC is considered aggressive cancer with bad prognosis and poor clinical outcomes. It lacks estrogen, progesterone, and ERBB2 receptors rendering its treatment more challenging. Owing to its unresponsiveness to hormonal therapy, quick tumor growth, and the high probability to have spread at the time of discovery, it is more likely to recur following therapy. Proteolysis Targeting Chimeric molecules (PROTACs) are hetero‐bifunctional molecules that are able to hijack the ubiquitin‐proteasome system, a major physiological proteolytic mechanism. This leads to ubiquitination through endogenous E3 ligases and subsequent degradation through 26‐S proteasome. Since its discovery in 2001, PROTACs have been considered an important therapeutic modality due to their ability to target and degrade undruggable proteins. In vitro studies have been conducted to investigate the possibility of using PROTACs as a therapeutic modality in TNBC. Data available propose great potential of PROTACs technology as a major candidate in TNBC management. Further in vitro and in vivo clinical trials are required to establish a definitive decision. In this review, we aim to give a brief overview of TNBC and PROTACs and highlight the rationale behind using PROTACs as a therapeutic modality in patients with TNBC.

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“…The first-generation inhibitors, such as flavopiridol, roscovitine, UNC-01, etc., due to the lack of selectivity for different types of CDK and serious side effects in the clinical, their development was stopped (97,98). On the contrary, the second generation of CDK inhibitors show better anti-tumor activity and selectivity, especially those targeting CDK4/6, like palbociclib, ribociclib, abemaciclib, etc., which can inhibit RB phosphorylation and block the cell cycle in G1 phase, preventing the proliferation of breast cancer (99,100). Clinical trials have shown that it has good efficacy in the treatment of metastatic breast cancer with HR+ and HER2when combined with endocrine therapy (101).…”

Section: Cdk Inhibitorsmentioning

confidence: 99%

New Advances in Targeted Therapy of HER2-Negative Breast Cancer

Peng

Xie

et al. 2022

Front. Oncol.

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Breast cancer has an extremely high incidence in women, and its morbidity and mortality rank first among female tumors. With the increasing development of molecular biology and genomics, molecular targeted therapy has become one of the most active areas in breast cancer treatment research and has also achieved remarkable achievements. However, molecular targeted therapy is mainly aimed at HER2-positive breast cancer and has not yet achieved satisfactory curative effect on HER2-negative breast cancer. This article describes the potential targets that may be used for breast cancer treatment from the aspects of PI3K/AKT signaling pathway, DDR, angiogenesis, the cell cycle, breast cancer stem cells, etc., and explores possible inhibitors for the treatment of HER2-negative breast cancer, such as PI3K inhibitors, AKT inhibitors and m-TOR inhibitors that inhibit the PI3K/AKT signaling pathway, small molecule tyrosine kinase inhibitors that restrain angiogenesis, CDK inhibitors, aurora kinase inhibitors and HDAC inhibitors that block cell cycle, as well as the drugs targeting breast cancer stem cells which have been a hit, aiming to provide a new idea and strategy for the treatment of HER2-negative breast cancer.

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CDK4/6 inhibitors: A potential therapeutic approach for triple negative breast cancer

Cited by 15 publications

References 142 publications

Comprehensive proteome and phosphoproteome analysis reveals the protein characterization of invasive ductal and lobular carcinoma with specific molecular subgroup

Comprehensive proteome and phosphoproteome analysis reveals the protein characterization of invasive ductal and lobular carcinoma with specific molecular subgroup

Proteolysis Targeting Chimera (PROTAC) as a promising novel therapeutic modality for the treatment of triple‐negative breast cancer (TNBC)

New Advances in Targeted Therapy of HER2-Negative Breast Cancer

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