scholarly journals Mechanisms of Resistance to Chemotherapy in Breast Cancer and Possible Targets in Drug Delivery Systems

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1193
Author(s):  
Patrícia de Faria Lainetti ◽  
Antonio Fernando Leis-Filho ◽  
Renee Laufer-Amorim ◽  
Alexandre Battazza ◽  
Carlos Eduardo Fonseca-Alves
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Integrative Approach ◽  
Cell Resistance ◽  
Chemotherapy Treatment ◽  
Mechanisms Of Resistance ◽  
Literature Information ◽  
Therapeutic Perspective ◽  
Resistance To Chemotherapy ◽  
Tumor Cell Resistance

Breast cancer (BC) is one of the most important cancers worldwide, and usually, chemotherapy can be used in an integrative approach. Usually, chemotherapy treatment is performed in association with surgery, radiation or hormone therapy, providing an increased outcome to patients. However, tumors can develop resistance to different drugs, progressing for a more aggressive phenotype. In this scenario, the use of nanocarriers could help to defeat tumor cell resistance, providing a new therapeutic perspective for patients. Thus, this systematic review aims to bring the molecular mechanisms involved in BC chemoresistance and extract from the previous literature information regarding the use of nanoparticles as potential treatment for chemoresistant breast cancer.

scholarly journals Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review

2019 ◽  
Vol 145 (5) ◽  
pp. 1179-1188 ◽  
Author(s):  
Kamal Pandey ◽  
Hee‐Jung An ◽  
Seung Ki Kim ◽  
Seung Ah Lee ◽  
Sewha Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Mechanisms ◽  
Mechanisms Of Resistance

Q-CROC-03: A prospective biopsy driven clinical trial to study the mechanisms of resistance to chemotherapy in triple-negative breast cancer patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS1139-TPS1139
Author(s):  
Adriana Aguilar-Mahecha ◽  
Josiane Lafleur ◽  
Carole Seguin ◽  
Catalin Liviu Dragos Mihalcioiu ◽  
Josee-Anne Roy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Limiting Factors ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Tumor Resistance ◽  
Cancer Subtypes ◽  
Resistance To Chemotherapy

TPS1139 Background: Resistance to chemotherapy or targeted agents is the cause of death in most patients dying of breast cancer and one of the major challenges presently faced by oncologists. In triple negative breast cancers (TNBCs), drug resistance emerges quicker than in other breast cancer subtypes and contributes to the poor prognosis seen in these patients. The lack of targeted therapies to treat TNBC highlights the important need to better understand the molecular mechanisms contributing to chemotherapy resistance in order to develop new therapeutic strategies. However, the difficulty in obtaining tissue samples from drug resistant tumors has been one of the limiting factors in this field of study. Methods: We have designed a prospective phase II clinical trial where paired biopsies are collected from chemotherapy resistant TNBCs (NCT01276899). Four needle core biopsies are collected before the initiation of treatment and 2 weeks before surgery or at the time of progression in the neoadjuvant and metastatic settings respectively. Metastatic sites eligible for biopsy include liver, lung, skin and lymph nodes. This study is presently recruiting at 5 major health centers in Quebec and will soon open in the USA. We have currently enrolled 13 patients in the neoadjuvant setting and 2 metastatic patients. Major challenges in patient enrolment will be discussed. We have standardized the methods of collection and processing of tissue and blood specimens to ensure their molecular integrity and compatibility with different genomic and proteomic molecular platforms. Analysis of tumor cellularity has been incorporated into our quality control and we have optimized the extraction of nucleic acids to obtain high yields and optimal quality. Paired biopsies will undergo Next Gen Sequencing, flow sorted aCGH analysis, gene expression and miRNA profiling as well as phosphoproteomic profiling using reverse phase protein arrays. Collection of clinical data will allow molecular profiling data to be linked to clinical response data so as to determine DNA, RNA and protein factors correlated with tumor resistance to chemotherapy.

scholarly journals Cisplatin-resistant triple-negative breast cancer subtypes: multiple mechanisms of resistance

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
David P. Hill ◽  
Akeena Harper ◽  
Joan Malcolm ◽  
Monica S. McAndrews ◽  
Susan M. Mockus ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Treatment Strategies ◽  
Heterogeneous Data ◽  
Variable Response ◽  
Mechanisms Of Resistance ◽  
Mesenchymal Transition ◽  
Cancer Subtypes

Abstract Background Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies. Methods In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated genes, evaluating their differential expression in the cisplatin-sensitive, basal-like 1 (BL1) and basal-like 2 (BL2) subtypes, and the two cisplatin-resistant, luminal androgen receptor (LAR) and mesenchymal (M) subtypes of TNBC. Results We found 20 genes that were differentially expressed in at least one subtype. Fifteen of the 20 genes are associated with cell death and are distributed among all TNBC subtypes. The less cisplatin-responsive LAR and M TNBC subtypes show different regulation of 13 genes compared to the more sensitive BL1 and BL2 subtypes. These 13 genes identify a variety of cisplatin-resistance mechanisms including increased transport and detoxification of cisplatin, and mis-regulation of the epithelial to mesenchymal transition. Conclusions We identified gene signatures in resistant TNBC subtypes indicative of mechanisms of cisplatin. Our results indicate that response to cisplatin in TNBC has a complex foundation based on impact of treatment on distinct cellular pathways. We find that examination of expression data in the context of heterogeneous data such as drug-gene interactions leads to a better understanding of mechanisms at work in cancer therapy response.

scholarly journals Inability of granule polarization by NK cells defines tumor resistance and can be overcome by CAR or ADCC mediated targeting

2021 ◽  
Vol 9 (1) ◽  
pp. e001334
Author(s):  
Jiri Eitler ◽  
Natalie Wotschel ◽  
Nicole Miller ◽  
Laurent Boissel ◽  
Hans G Klingemann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cell ◽  
Nk Cells ◽  
Cancer Cells ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Nk Cell ◽  
Live Cell ◽  
Cell Resistance ◽  
Tumor Cell Resistance

BackgroundOn encountering a susceptible target, natural killer (NK) cells mediate cytotoxicity through highly regulated steps of directed degranulation. Cytotoxic granules converge at the microtubule organizing center and are polarized toward the immunological synapse (IS), followed by granule exocytosis. NK cell retargeting by chimeric antigen receptors (CARs) or mAbs represents a promising strategy for overcoming tumor cell resistance. However, little is known about the lytic granule dynamics of such retargeted NK cells toward NK-cell-resistant tumors.MethodsHere, we used spinning disk confocal microscopy for live-cell imaging to analyze granule-mediated NK cell cytotoxicity in ErbB2-targeted CAR-expressing NK-92 cells (NK-92/5.28.z) and high-affinity FcR transgenic NK-92 cells plus Herceptin toward ErbB2-positive breast cancer cells (MDA-MB-453), which are resistant to parental NK-92.ResultsUnmodified NK-92 cells cocultured with resistant cancer cells showed stable conjugate formation and granule clustering, but failed to polarize granules to the IS. In contrast, retargeting by CAR or FcR+Herceptin toward the MDA-MB-453 cells enabled granule polarization to the IS, resulting in highly effective cytotoxicity. We found that in NK-92 the phosphoinositide 3-kinase pathway was activated after contact with resistant MDA-MB-453, while phospholipase C-γ (PLCγ) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) were not activated. In contrast, retargeting by CAR or antibody-dependent cell-mediated cytotoxicity (ADCC) provided the missing PLCγ and MEK/ERK signals.ConclusionsThese observations suggest that NK cells can create conjugates with resistant cancer cells and respond by granule clustering, but the activation signals are insufficient to induce granule polarization and consequent release of lytic enzymes. Retargeting by CAR and/or the FcR/mAb (ADCC) axis provide the necessary signals, leading to granule polarization and thereby overcoming tumor cell resistance.Keywords: NK cells, NK-92, haNK, ADCC, Chimeric Antigen Receptor (CAR), breast cancer, cancer immunotherapy, live-cell imaging, granule polarization

Anticipating mechanisms of resistance to PI3K inhibition in breast cancer: a challenge in the era of precision medicine

2014 ◽  
Vol 42 (4) ◽  
pp. 733-741 ◽  
Author(s):  
Cedric Leroy ◽  
Romain J. Amante ◽  
Mohamed Bentires-Alj
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Pik3ca Mutation ◽  
Mechanisms Of Resistance ◽  
Combination Treatments ◽  
Development Of Resistance ◽  
Pi3k Inhibition ◽  
Pi3k Signalling ◽  
Phosphoinositide 3 Kinase

Frequent subversion of the PI3K (phosphoinositide 3-kinase) pathway during neoplastic transformation contributes to several hallmarks of cancer that result in a competitive advantage for cancer cells. Deregulation of this pathway can be the result of genomic alterations such as PIK3CA mutation, PTEN (phosphatase and tensin homologue deleted on chromosome 10) loss or the activation of upstream protein tyrosine kinases. Not surprisingly, the PI3K signalling pathway has become an attractive therapeutic target, and numerous inhibitors are in clinical trials. Unfortunately, current therapies for advanced cancers that target PI3K often lead to the development of resistance and relapse of the disease. It is therefore important to establish the molecular mechanisms of resistance to PI3K-targeted therapy. With the focus on breast cancer, in the present article, we summarize the different ways of targeting PI3K, review potential mechanisms of resistance to PI3K inhibition and discuss the rationale of combination treatments to reach a balance between efficacy and toxicity.

Mechanisms of resistance to endocrine therapies for breast cancer

2012 ◽  
Vol 9 (2) ◽  
Author(s):  
Pierre Heudel ◽  
Paul Vilquin ◽  
Olivier Tredan ◽  
Isabelle Ray-Coquard ◽  
Jean-Paul Guastalla ◽  
...  
Keyword(s):  
Public Health ◽  
Breast Cancer ◽  
Prognostic Factors ◽  
Molecular Mechanisms ◽  
Health Concern ◽  
Breast Cancers ◽  
Human Breast ◽  
Mechanisms Of Resistance ◽  
Public Health Concern ◽  
Clinical Models

AbstractBreast cancer is the most frequently diagnosed cancer in women and 70% of the cases are hormone-dependent. The presence of ERα is one of the most important prognostic factors predictive of response to endocrine therapy in human breast cancers. Resistance to endocrine therapies has become a major public health concern and it appears essential to understand the mechanisms underlying this phenomenon. This review provides insights into the molecular mechanisms associated with resistance to endocrine therapies and presents the different strategies currently developed in pre-clinical models to overcome this resistance.

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