https://orcid.org/0000-0002-2810-6128
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ABSTRACT
Introduction
Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2) and often associated with poor survival outcomes. The backbone of current treatments for TNBC relies on chemotherapy; however, resistance to cytotoxic agents is a commonly encountered hurdle to overcome.
Areas covered
Current understanding on the mechanisms involved in TNBC chemoresistance is evaluated and novel potential actionable targets and recently explored modalities for carrying and delivering chemotherapeutics are highlighted.
Expert opinion
A comprehensive identification of both genomic and functional TNBC signatures is required for a more definite categorization of the patients in order to prevent insensitivity to chemotherapy and therefore realize the full potential of precision-medicine approaches. In this scenario, cell-line-derived xenografts (CDX), patient-derived xenografts (PDX), patient-derived orthotopic xenografts (PDOX), and patient-derived organoids (PDO) are indispensable experimental models for evaluating the efficacy of drug candidates and predicting the therapeutic response. The combination of increasingly sensitive ‘omics’ technologies, computational algorithms, and innovative drug modalities may accelerate the successful translation of novel candidate TNBC targets from basic research to clinical settings, thus contributing to reach optimal clinical output, with lower side effects and reduced resistance.
Article highlights
Chemoresistance in triple-negative breast cancer (TNBC) frequently occurs and leads to poor overall survival. The heterogeneity in the TNBC biology, which is reflected in a variety of therapeutic responses and long-term outcomes, delayed the development of systemic treatment options in unselected patient groups and therefore made this setting particularly challenging.
Different and interrelated mechanisms can drive drug resistance in TNBC. They include cancer stem cell self-renewal, pro-tumorigenic signals in both cancer cells and the surrounding microenvironment, altered DNA repair mechanisms, evasion of apoptosis, metabolic changes, and overexpression of ATP binding cassette transporters.
Fascinating therapeutic opportunities for TNBC are found on novel recently identified suitable molecular targets that are acknowledged as prognostic biomarkers and/or important effectors of TNBC progression, including oncogenic signaling mediators, hypoxic and pro-inflammatory molecules, among others.
The translation of promising drug targets from basic research to clinical settings along with the characterization of molecular distinctive features that may drive personalized therapeutic approaches and the improvement of drug delivery technologies may open up potential therapeutic avenues for overcoming chemoresistance and improving patient outcome.
This box summarizes key points contained in the article.
List of Abbreviations
| ABC Transporters | = | ATP-binding cassette transporters. |
| ADCs | = | antibody drug conjugates. |
| AKT | = | protein kinase B. |
| AR | = | androgen receptor. |
| ATM | = | ataxia-telangiectasia-mutated. |
| ATR | = | ataxia–telangiectasia and Rad3-related. |
| BC | = | breast cancer. |
| BCL | = | B-cell lymphoma. |
| BCRP: | = | breast cancer resistance protein. |
| BET | = | bromodomain extra-terminal domain. |
| BL1 | = | basal-like 1. |
| BL2 | = | basal-like 2. |
| BLM | = | bloomhelicase. |
| CA IX | = | carbonic anhydrase. |
| CAFs | = | cancer-associated fibroblasts. |
| CCL2 | = | C-C Motif Chemokine Ligand 2. |
| CCL5 | = | C-C Motif Chemokine Ligand 5. |
| CSC | = | cancer stem cell. |
| DAMPs | = | damage associated molecular patterns. |
| DDFS | = | distant disease-free survival. |
| DDR | = | DNA damage–response. |
| DFS | = | disease-free survival. |
| DHT | = | dihydrotestosterone. |
| DXT | = | docetaxel. |
| ECM | = | extracellular matrix. |
| EGFR | = | epidermal growth factor receptor. |
| EMT | = | epithelial-mesenchymal transition. |
| ER | = | estrogen receptor. |
| ESMO | = | European Society for Medical Oncology |
| EVs | = | extracellular vesicles |
| FAK | = | focal adhesion kinase. |
| FANCI | = | fanconi anemia complementation group I. |
| FASN | = | fatty acid synthase |
| FDA | = | Food and Drug Administration. |
| FGFR1 | = | fibroblast growth factor receptor 1 |
| FN1 | = | fibronectin. |
| FOXM1 | = | forkhead box M1 |
| GF | = | growth factor. |
| GPER | = | G-protein coupled estrogen receptor |
| GR | = | glucocorticoid receptor. |
| HER2 | = | human epidermal growth factor 2 protein |
| HIF | = | hypoxia-inducible factor. |
| HR | = | hormone receptor. |
| ICAM-1 | = | intercellular adhesion molecule 1. |
| ICD | = | immunogenic cell death. |
| ICIs | = | immune checkpoint inhibitors |
| IL-1β | = | interleukin-1 beta. |
| IL-6 | = | interleukin-6. |
| IL-8 | = | interleukin-8. |
| IM | = | immunomodulatory. |
| ITGA5 | = | integrin alpha |
| JAK | = | Janus kinase. |
| KISS1R | = | G protein-coupled kisspeptin receptor. |
| LAR | = | luminal androgen receptor. |
| LDHA | = | lactate dehydrogenase A. |
| LFA-1 | = | lymphocyte function-associated antigen 1. |
| LOX | = | lysyl oxidase. |
| LRFS | = | loco-regional-free survival. |
| MAPK | = | of mitogen-activated protein kinase. |
| MCL-1 | = | myeloid cell leukemia-1. |
| MDR | = | multi-drug resistance. |
| MLK4 | = | mixed-lineage kinase 4. |
| MRP1 | = | multidrug-resistant protein-1. |
| MRP4 | = | multiple drug resistance-associated protein 4. |
| MRP8 | = | multidrug-resistant protein-8. |
| MSL | = | mesenchymal stem–like. |
| mTOR | = | mammalian target of the rapamycin. |
| NFκB | = | nuclear factor-kappa B. |
| OBR | = | leptin receptor. |
| OS | = | overall survival. |
| OXPHOS | = | oxidative phosphorylation. |
| P4H | = | HIF-prolyl 4-hydroxylase. |
| PARP | = | poly-ADP-ribose polymerase. |
| PARPi | = | PARP inhibitors. |
| pCR | = | pathologic complete response. |
| PD-L1 | = | programmed death ligand |
| PDT | = | photodynamic therapy. |
| PFS | = | progression-free survival. |
| PR | = | progesterone receptor. |
| PHGDH | = | phosphoglycerate dehydrogenase. |
| PI3K | = | phosphatidylinositol 3-kinase. |
| PIK3CA | = | phosphatidylinositol-4-5-bisphosphate-3-kinase catalytic subunit-α. |
| RASA4 | = | ras GTPase-activating protein 4 |
| ROS | = | reactive oxygen species. |
| RNAi: | = | RNA-interference. |
| RNF5 | = | ring finger protein 5 |
| S1P | = | sphingosine-1-phosphate. |
| SRD5A1 | = | type-1 isoform of the steroid-5alpha-reductase. |
| STAT3 | = | signal transducer and activator of transcription 3. |
| TAMs | = | tumor-associated macrophages. |
| TAZ | = | transcriptional co-activator with PDZ-binding motif |
| tDRs | = | transfer RNA-derived fragments. |
| TGF-β | = | transforming growth factor beta. |
| TILs | = | tumor infiltrating lymphocytes. |
| TME | = | tumor microenvironment. |
| TNBC | = | triple negative breast cancer. |
| TNFα | = | tumor necrosis factor α. |
| TRAIL | = | TNF-related apoptosis-inducing ligand. |
| TRIM-37 | = | tripartite motif-containing protein 37. |
| TROP-2 | = | trophoblast cell-surface antigen. |
| TRPC3 | = | transient receptor potential cation channel subfamily C member 3. |
| VEGF | = | vascular-endothelial growth factor. |
| XIAP | = | X-linked inhibitor of apoptosis protein. |
| YAP | = | YES-associated protein. |
| ZEB1 | = | zinc finger E-box binding homeobox 1. |
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose