scholarly journals Mechanisms of CDK4/6 Inhibitor Resistance in Luminal Breast Cancer

2020 ◽  
Vol 11 ◽  
Author(s):  
Zhen Li ◽  
Wei Zou ◽  
Ji Zhang ◽  
Yunjiao Zhang ◽  
Qi Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Cancer Drug ◽  
Luminal Breast Cancer ◽  
Cancer Drug Resistance ◽  
Estrogen Receptor Positive ◽  
Underlying Mechanisms ◽  
Inhibitor Resistance ◽  
New Generation

As a new-generation CDK inhibitor, a CDK4/6 inhibitor combined with endocrine therapy has been successful in the treatment of advanced estrogen receptor–positive (ER+) breast cancer. Although there has been overall progress in the treatment of cancer, drug resistance is an emerging cause for breast cancer–related death. Overcoming CDK4/6 resistance is an urgent problem. Overactivation of the cyclin-CDK-Rb axis related to uncontrolled cell proliferation is the main cause of CDK4/6 inhibitor resistance; however, the underlying mechanisms need to be clarified further. We review various resistance mechanisms of CDK4/6 inhibitors in luminal breast cancer. The cell signaling pathways involved in therapy resistance are divided into two groups: upstream response mechanisms and downstream bypass mechanisms. Finally, we discuss possible strategies to overcome CDK4/6 inhibitor resistance and identify novel resistance targets for future clinical application.

scholarly journals Estrogen-regulated feedback loop limits the efficacy of estrogen receptor–targeted breast cancer therapy

2018 ◽  
Vol 115 (31) ◽  
pp. 7869-7878 ◽  
Author(s):  
Tengfei Xiao ◽  
Wei Li ◽  
Xiaoqing Wang ◽  
Han Xu ◽  
Jixin Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Therapy Resistance ◽  
Negative Feedback Loop ◽  
Endocrine Therapy Resistance ◽  
Estrogen Receptor Positive ◽  
Underlying Mechanisms

Endocrine therapy resistance invariably develops in advanced estrogen receptor-positive (ER+) breast cancer, but the underlying mechanisms are largely unknown. We have identified C-terminal SRC kinase (CSK) as a critical node in a previously unappreciated negative feedback loop that limits the efficacy of current ER-targeted therapies. Estrogen directly drives CSK expression in ER+ breast cancer. At low CSK levels, as is the case in patients with ER+ breast cancer resistant to endocrine therapy and with the poorest outcomes, the p21 protein-activated kinase 2 (PAK2) becomes activated and drives estrogen-independent growth. PAK2 overexpression is also associated with endocrine therapy resistance and worse clinical outcome, and the combination of a PAK2 inhibitor with an ER antagonist synergistically suppressed breast tumor growth. Clinical approaches to endocrine therapy-resistant breast cancer must overcome the loss of this estrogen-induced negative feedback loop that normally constrains the growth of ER+ tumors.

scholarly journals The Role of Non-Coding RNAs in Breast Cancer Drug Resistance

2021 ◽  
Vol 11 ◽  
Author(s):  
Jin-hai Tian ◽  
Shi-hai Liu ◽  
Chuan-yang Yu ◽  
Li-gang Wu ◽  
Li-bin Wang
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Tumor Development ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Cancer Drug ◽  
Circular Rnas ◽  
Mortality And Morbidity ◽  
Micro Rnas ◽  
Non Coding Rnas

Breast cancer (BC) is one of the commonly occurring malignancies in females worldwide. Despite significant advances in therapeutics, the mortality and morbidity of BC still lead to low survival and poor prognosis due to the drug resistance. There are certain chemotherapeutic, endocrine, and target medicines often used for BC patients, including anthracyclines, taxanes, docetaxel, cisplatin, and fluorouracil. The drug resistance mechanisms of these medicines are complicated and have not been fully elucidated. It was reported that non-coding RNAs (ncRNAs), such as micro RNAs (miRNA), long-chain non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) performed key roles in regulating tumor development and mediating therapy resistance. However, the mechanism of these ncRNAs in BC chemotherapeutic, endocrine, and targeted drug resistance was different. This review aims to reveal the mechanism and potential functions of ncRNAs in BC drug resistance and to highlight the ncRNAs as a novel target for achieving improved treatment outcomes for BC patients.

Clinical applications of circulating tumor DNA in monitoring breast cancer drug resistance

2020 ◽  
Vol 16 (34) ◽  
pp. 2863-2878
Author(s):  
Yang Liu ◽  
Qian Du ◽  
Dan Sun ◽  
Ruiying Han ◽  
Mengmeng Teng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Clinical Applications ◽  
Current Status ◽  
Cancer Drug ◽  
Genomic Alteration ◽  
Tumor Dna

Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. Unfortunately, treatments often fail because of the development of drug resistance, the underlying mechanisms of which remain unclear. Circulating tumor DNA (ctDNA) is free DNA released into the blood by necrosis, apoptosis or direct secretion by tumor cells. In contrast to repeated, highly invasive tumor biopsies, ctDNA reflects all molecular alterations of tumors dynamically and captures both spatial and temporal tumor heterogeneity. Highly sensitive technologies, including personalized digital PCR and deep sequencing, make it possible to monitor response to therapies, predict drug resistance and tailor treatment regimens by identifying the genomic alteration profile of ctDNA, thereby achieving precision medicine. This review focuses on the current status of ctDNA biology, the technologies used to detect ctDNA and the potential clinical applications of identifying drug resistance mechanisms by detecting tumor-specific genomic alterations in breast cancer.

scholarly journals Targeted sequencing reveals the somatic mutation landscape in a Swedish breast cancer cohort

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Argyri Mathioudaki ◽  
Viktor Ljungström ◽  
Malin Melin ◽  
Maja Louise Arendt ◽  
Jessika Nordin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Somatic Mutation ◽  
Age Of Onset ◽  
Single Nucleotide Variants ◽  
Modifying Genes ◽  
Dna Mismatch ◽  
Targeted Next Generation Sequencing ◽  
Estrogen Receptor Positive ◽  
Underlying Mechanisms ◽  
Swedish Cohort

Abstract Breast cancer (BC) is a genetically heterogeneous disease with high prevalence in Northern Europe. However, there has been no detailed investigation into the Scandinavian somatic landscape. Here, in a homogeneous Swedish cohort, we describe the somatic events underlying BC, leveraging a targeted next-generation sequencing approach. We designed a 20.5 Mb array targeting coding and regulatory regions of genes with a known role in BC (n = 765). The selected genes were either from human BC studies (n = 294) or from within canine mammary tumor associated regions (n = 471). A set of predominantly estrogen receptor positive tumors (ER +  85%) and their normal tissue counterparts (n= 61) were sequenced to ~ 140 × and 85 × mean target coverage, respectively. MuTect2 and VarScan2 were employed to detect single nucleotide variants (SNVs) and copy number aberrations (CNAs), while MutSigCV (SNVs) and GISTIC (CNAs) algorithms estimated the significance of recurrent somatic events. The significantly mutated genes (q ≤ 0.01) were PIK3CA (28% of patients), TP53 (21%) and CDH1 (11%). However, histone modifying genes contained the largest number of variants (KMT2C and ARID1A, together 28%). Mutations in KMT2C were mutually exclusive with PI3KCA mutations (p ≤ 0. 001) and half of these affect the formation of a functional PHD domain. The tumor suppressor CDK10 was deleted in 80% of the cohort while the oncogene MDM4 was amplified. Mutational signature analyses pointed towards APOBEC deaminase activity (COSMIC signature 2) and DNA mismatch repair (COSMIC signature 6). We noticed two significantly distinct patterns related to patient age; TP53 being more mutated in the younger group (29% vs 9% of patients) and CDH23 mutations were absent from the older group. The increased somatic mutation prevalence in the histone modifying genes KMT2C and ARID1A distinguishes the Swedish cohort from previous studies. KMT2C regulates enhancer activation and assists tumor proliferation in a hormone-rich environment, possibly pointing to a role in ER + BC, especially in older cases. Finally, age of onset appears to affect the mutational landscape suggesting that a larger age-diverse population incorporating more molecular subtypes should be studied to elucidate the underlying mechanisms.

scholarly journals Cell line-specific network models of ER+ breast cancer identify potential PI3Kα inhibitor resistance mechanisms and drug combinations

2021 ◽  
pp. canres.1208.2021
Author(s):  
Jorge Gómez Tejeda Zañudo ◽  
Pingping Mao ◽  
Clara Alcon ◽  
Kailey Kowalski ◽  
Gabriela N Johnson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Network Models ◽  
Resistance Mechanisms ◽  
Drug Combinations ◽  
Inhibitor Resistance

scholarly journals Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance

2012 ◽  
Vol 83 (8) ◽  
pp. 1084-1103 ◽  
Author(s):  
Karthika Natarajan ◽  
Yi Xie ◽  
Maria R. Baer ◽  
Douglas D. Ross
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Breast Cancer Resistance Protein ◽  
Cancer Drug ◽  
Cancer Resistance ◽  
Cancer Drug Resistance ◽  
Resistance Protein

Breast Cancer Drug Resistance

2011 ◽  
pp. 497-503
Author(s):  
Christina L. Addison ◽  
Miguel A. Cabrita
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Drug ◽  
Cancer Drug Resistance

Breast Cancer Drug Resistance

2014 ◽  
pp. 1-11
Author(s):  
Christina L. Addison ◽  
Miguel A. Cabrita
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Drug ◽  
Cancer Drug Resistance
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