Although the use of this ADC in a pretreated patient population with HER2+ metastatic BC showed durable antitumor activity, the efficacy of this ADC in HER2+ metastatic BC patients previously treated with TDM-1 needs to be confirmed.88 Trastuzumab deruxtecan is also being evaluated for the treatment of metastatic BC in patients with low HER2 expression, for whom current available therapies targeting HER2 are ineffective. Cancer I ncidence in F ive C ontinents: inclusion criteria, highlights from Volume X and the global status of cancer registration. Drug reuse or repositioning refers to the process of seeking new medical treatments within available medications, rather than developing new medications.59 This strategy reduces the approval time for drug use and increases the success of clinical development. Keywords: Chromosomal aberration in the post-implantation embryos sired by tamoxifen treated male rats, Endocrine resistance in breast cancer: from cellular signaling pathways to epigenetic mechanisms, Tamoxifen resistance: from cell culture experiments towards novel biomarkers. Careers, Unable to load your collection due to an error. Fatigue Causes - Mayo Clinic Front Genet. Anastrozole and letrozole are non-steroidal AIs, while exemestane is a steroidal AI.38 Although these three compounds have been shown to suppress overall plasma and tissue estrogens by >90%, some studies suggest that letrozole is the most potent of the nonsteroidal compounds.39, In metastatic BC, these AIs can be used sequentially and cause new responses in selected patients after resistance to the first treatment. Dueas-Gonzalez A, Coronel J, Cetina L, Gonzlez-Fierro A, Chavez-Blanco A, Taja-Chayeb L. Hydralazine-valproate: a repositioned drug combination for the epigenetic therapy of cancer, Cytokine-mediated therapeutic resistance in breast cancer, Mechanisms of resistance to neoadjuvant chemotherapy in breast cancer, Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal. Yurkovetskiy A, Gumerov D, Ter-Ovanesyan E, et al. (B) Acquired resistance to TAM involves alterations in translation signals by increasing the expression and activity of tyrosine kinase receptor family proteins, such as HER2, EGFR, IGFR and GPR30. Additionally, hypoxia is a trigger for tumor resistance to chemotherapy, since it leads to both decreased DNA topoisomerase II alpha (TOP2A) expression and upregulation of MRP. In the PALOMA-3 trial, the addition of palbociclib to FUL resulted in a prolongation of overall survival of 6.9 months among patients with advanced ER+/HER2- BC who showed disease progression after prior endocrine therapy.50 In the MONARCH-2 and MONALEESA-3 clinical trials, the combination of FUL with abemaciclib or ribociclib, respectively, resulted in an improvement in both progression-free survival and overall survival.50,51, Despite the benefits of CDK4/6 inhibitors, some adverse effects have been observed, including hematological toxicities, mainly neutropenia, and non-hematological toxicities such as fatigue, nausea, vomiting, stomatitis, alopecia, skin rash, diarrhea, decreased appetite, and infections. Antitumor effects of lidocaine on human breast cancer cells: an in vitro and in vivo experimental trial. 2015;137(9):20602071. Standard therapy for the treatment of ER+ BC is typically based on the use of endocrine therapy (TAM, FUL, and AIs). Early Breast Cancer Trialists Collaborative Group (EBCTCG). eCollection 2022. Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ. sharing sensitive information, make sure youre on a federal This collision leads to the obstruction in the flow of electrons Additionally, the mTOR inhibitor everolimus (Afinitor) (Figure 1) overcomes resistance to hormone therapy by controlling the AKT/mTOR signaling pathway.57 Furthermore, recent studies showed the benefit of everolimus with CDK4/6 inhibitor treatment in ER+ metastatic BC patients.58. Inclusion in an NLM database does not imply endorsement of, or agreement with, -, Harbeck N, Cortes J, Gnant M, et al. Pantziarka P, Bryan BA, Crispino S, Dickerson EB. Frontiers | The Influencing Factors of Bacterial Resistance Additionally, another study reported that PI3K/AKT/mTOR inhibitors in combination with trastuzumab or trastuzumab and paclitaxel were efficient and safe for patients and showed beneficial anti-tumor activities.86, ADCs are a means of delivering cytotoxic drugs specifically to cancer cells. Bian X, Liang Z, Feng A, Salgado E, Shim H. HDAC inhibitor suppresses proliferation and invasion of breast cancer cells through regulation of miR-200c targeting CRKL, The microRNA miR-181c enhances chemosensitivity and reduces chemoresistance in breast cancer cells via down-regulating osteopontin, MiR-873/PD-L1 axis regulates the stemness of breast cancer cells. Additionally, emerging treatments that seek to overcome resistance and reduce side effects are also described. G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer, Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic, AIB1 is required for the acquisition of epithelial growth factor receptor-mediated tamoxifen resistance in breast cancer cells, The genomic landscape of endocrine-resistant advanced breast cancers, Mechanisms of resistance to selective estrogen receptor down-regulator in metastatic breast cancer, PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Kedia-Mokashi N, Makawy AEL, Saxena M, Balasinor NH. One of the most significant clinical problems in the treatment of patients with BC is the development of therapeutic resistance. -. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. Implementation of genomics edition by CRISPR system has provided a glimpse of broad cellular heterogeneity and the opportunity to act on tumor cells with mutant alleles,133,134 such as alterations in EGFR, KRAS, BAP1, BRAF, BRCA1, and BRCA2, or with replicative immortality without affecting normal cells.133,135 The CRISPR system (CRISPR/Cas9) has been established in preclinical trials as an effective tool to specifically attack and/or resensitize tumor cells.136, Potential targets have been identified in BC through CRISPR/Cas9, including microtubule affinity regulating kinase 4 (MARK4) and fermitin family homolog-2 (FERMT2), which are related to metastasis; microtubule-associated serine/threonine kinase (MASTL), which is involved in cell proliferation; the tyrosine protein kinase FYN that is involved in drug resistance; and cyclin-dependent kinase 7 (CDK7), which is negatively associated with tumor size and grade.135 CRISPR/Cas9 has also been used to generate changes in exons of the HER2 gene. MDR1 gene is significantly overexpressed in multidrug resistance phenotype114 (Figure 3C). Front Mol Biosci. eCollection 2023. Such changes lead to the expression of a truncated HER2 protein that prevents dimerization of the transmembrane domain, leading to inhibition of signaling pathways such as MAPK/ERK and PI3K/AKT, as well as cell proliferation and tumorigenicity.134 As with immunotherapy, CRISPR/Cas9 can also target stromal cells in the tumor microenvironment to generate mutations in VEGF and VEGFR2, thereby inhibiting stromal cell migration activity.136, Exosomes, an important class of extracellular vesicles, transport and distribute biological macromolecules, such as proteins, nucleic acids, and anti-tumor drugs, and are considered promising therapeutic strategies for targeted drug delivery in BC.137 The therapeutic potential of exosomes as nano-transporters of DOX has been considered as a strategy to overcome resistance to chemotherapy.138 The use of exosomes could allow the targeted administration of drugs, overcoming several limitations associated with conventional nanoparticles, including cytotoxicity, drug modification, greater synergistic effects, and biocompatibility, among others.107,112,113. Castellanos G, Valbuena DS, Prez E, Villegas VE, Rondn-Lagos M. Breast Cancer (Dove Med Press). LINC00426 is a potential immune phenotype-related biomarker and an overall survival predictor in PAM50 luminal B breast cancer. Biparatopic anti-HER2 drug radioconjugates as breast cancer theranostics. ( A ) Effusion, MeSH For HER2+ tumors (luminal B and HER2+), treatment involves the use of monoclonal antibodies that recognize the extracellular domain of HER2 (trastuzumab) and inhibitors of the tyrosine kinase domain of HER2 (such as lapatinib), or even RNAi-mediated silencing,9 as well as endocrine therapy in cases with positive hormone receptors. Waters EA, McNeel TS, Stevens WM, Freedman AN. There are various causes for drug resistance in MM (Figure 3): (1) genetic alteration; (2) epigenetic alterations [20,115,116]; (3) abnormal drug transport and Ponnusamy L, Mahalingaiah PKS, Chang YW, Singh KP. Buparlisib is an orally available pan-PI3Ki and the most clinically advanced agent in this class. Should all patients with HR-positive HER2-negative metastatic breast cancer receive CDK 4/6 inhibitor as first-line based therapy? Careers. Although this has been a successful approach, some patients relapse and/or eventually develop resistance to treatment. Skidmore L, Sakamuri S, Knudsen N, et al. The results of trastuzumab deruxtecan treatment in these patients have shown a response rate of 44.2%.91. The .gov means its official. Listen to Resistance Is Fertile by Mamaguroove on Apple Music. Sarah Huckabee Sanders to limit teaching about race. NDLS is a new formulation of lipid-based, polysorbate 80 and ethanol-free formulation of docetaxel developed to overcome toxicity problems.132 The function of NDLS is based on its ability to infiltrate and become entrapped in the damaged tumor vasculature and collagen material of necrotic tumor tissue, leading to increased drug retention (leading to an enhanced permeability and retention effect).106 NDLS showed comparable efficacy and tolerability to conventional DOC in the treatment of metastatic BC in both prospective and retrospective studies.132 A recent study demonstrated that NDLS-based chemotherapy was effective and well tolerated in the treatment of patients with BC in all settings (neoadjuvant, adjuvant, and metastatic).106 The efficacy of NDLS is currently being prospectively evaluated in patients with TNBC (ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT03671044","term_id":"NCT03671044"}}NCT03671044). Doxorubicin resistance in breast cancer: a novel role for the human protein AHNAK, A review of the efficacy and safety of docetaxel as monotherapy in metastatic breast cancer, Novel targeted therapies for metastatic breast cancer. Fontes-Sousa M, Amorim M, Salta S, Palma De Sousa S, Henrique R, Jernimo C. Oncol Rep. 2019 Mar;41(3):1431-1438. doi: 10.3892/or.2019.6967. Abbreviations: ER+, estrogen receptor positive; ER-, estrogen receptor negative; TNBC, triple negative breast cancer. HHS Vulnerability Disclosure, Help Clinical evaluation of the use of exemestane as further hormonal therapy after nonsteroidal aromatase inhibitors in postmenopausal metastatic breast cancer patients. BC is a heterogeneous disease in which each patient has individual characteristics, which has led to the search for new markers to improve not only the diagnosis but also the prognosis and to achieve a better treatment response. Frontiers | Type M Resistance to Macrolides Is Due to a Two Other mAbs, such as aflibercept (a recombinant fusion protein) and pazopanib (a TKI) have shown good results in the inhibition of BC tumor cell migration and metastasis. 2016 Sep 27;7(39):64431-64446. doi: 10.18632/oncotarget.7043. Received 2020 Jul 5; Accepted 2020 Sep 15. official website and that any information you provide is encrypted Residents of the northern Ukrainian city of Chernihiv gathered at makeshift memorials on Indiscriminate Waste Disposal and Health Hazards in Chin YS, Beresford MJ, Ravichandran D, Makris A. Exemestane after non-steroidal aromatase inhibitors for post-menopausal women with advanced breast cancer, Forging a signature of in vivo senescence. The combination of pictilisib and FUL in patients with postmenopausal metastatic BC previously treated with an AI was evaluated in a randomized Phase II clinical trial (FERGI, {"type":"clinical-trial","attrs":{"text":"NCT01437566","term_id":"NCT01437566"}}NCT01437566). Mechanisms of resistance to endocrine therapy with tamoxifen (TAM) in breast cancer. Therefore, elucidating the molecular mechanisms involved in drug resistance is critical. Standard therapy for the treatment of ER+ BC is typically based on the use of endocrine therapy (TAM, FUL, and AIs). Subramanian S, Prasanna R, Biswas G, et al. DOX intercalates into DNA, preventing TOP2A binding and causing replication fork blockage,117 which eventually leads to apoptosis.10 DOX is used as the first-line treatment in BC and primarily for the treatment of advanced BC with an overall response rate of 30%50%,120 alone or in combination therapy with paclitaxel,110 docetaxel (DOC), cyclophosphamide, 5-fluorouracil, trifluridine, or vorinostat. For example, IL-8 leads to increased NFB and is involved in the activation of survival pathways such as those mediated by tumor necrosis factor receptor 2 (TNFR2), whereas high levels of IL-17A lead to increased cell proliferation and thus resistance.117, Considering that TNBC has the highest frequency of mutations and therefore the highest possibility of expressing immunogenic neoantigens, this BC subtype is considered to have the highest probability of responding to immunotherapy.123 Cancer immunotherapy aims to overcome the ability of tumor cells to resist the endogenous immune response by stimulating the patients immune system. The use of these inhibitors in combination with AI as first-line therapy or with FUL as second-line therapy in ER+/HER2- metastatic BC has shown improved progression-free survival in Phase III trials.12,44,45 However, abemaciclib is the only inhibitor among the three CDK4/6 inhibitors that has received FDA approval as monotherapy in ER+/HER2- metastatic BC, indicating its high potential as a single agent.46,47, Several phase III trials, such as the PALOMA-3 trial (FUL + palbociclib/placebo),48 the MONARCH-2 trial (FUL + abemaciclib/placebo),44 and the MONALEESA-3 trial (FUL with or without ribociclib),49 have demonstrated the efficacy of the combination of FUL and CDK4/6 inhibitors. Nanotechnological approaches are being developed to minimize the toxicity in healthy tissues generated by targeted therapy while maintaining the efficacy of the treatments. Solution Resistance - Higher tier. Stream songs including "Pallid Sky", "Rare to Find" and more. One study showed that 19H6-Hu in combination with trastuzumab was more effective at blocking phosphorylation of ERK1/2, AKT (S473) and HER2 (Y1248) in HER2+ BC cells compared with trastuzumab alone or in combination with pertuzumab.83, PI3K inhibitors are used in combination with AIs for the treatment of metastatic BC.84 However, most PI3K inhibitors are more toxic than beneficial. Additionally, emerging treatments that seek to overcome resistance and reduce side effects are also described. Mechanisms leading to the generation of resistance to chemotherapy. Before The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Park S-H, Chung YM, Ma J, Yang Q, Berek JS, Hu MCT. and transmitted securely. Overview of resistance to systemic therapy in patients with breast cancer. Length. Mehmood S, Faheem M, Ismail H, Farhat SM, Ali M, Younis S, Asghar MN. Herdiana Y, Wathoni N, Gozali D, Shamsuddin S, Muchtaridi M. Pharmaceutics. This review is focused on recent studies on the possible biological and molecular mechanisms involved in both response and resistance to treatment in BC. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase, Triglyceride deposit cardiomyovasculopathy: a rare cardiovascular disorder, Phase I study of ONT-380, a HER2 inhibitor, in patients with HER2+-advanced solid tumors, with an expansion cohort in HER2+ metastatic breast cancer (MBC), Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study, Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer, A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1). Cancer Today; 2018. 2. The .gov means its official. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93, The dynamic structure of the estrogen receptor. This hypothesis is inconsistent with the lack of resistance observed under hypoxia, as are the hypotheses that resistance is caused by increased repair of the eCollection 2023. Oncotarget. En, Changes in serum estrogenic activity during neoadjuvant therapy with letrozole and exemestane, Letrozole is superior to anastrozole in suppressing breast cancer tissue and plasma estrogen levels. Antibiotic resistance is one of the fastest-growing threats to global health. For example, patients with ER-positive (ER+) tumors receive endocrine therapy, and a small fraction of these patients also receive chemotherapy. See this image and copyright information in PMC. The authors also thank Gabrielle White Wolf, PhD, from Edanz Group (https://en-author-services.edanzgroup.com/ac) for editing a draft of this manuscript. 2015 Apr;16(4):16. doi: 10.1007/s11864-015-0334-8. What is the cause of resistance? - Physics Stack Exchange The school district in Little Rock, Ark., is resisting efforts by the administration of Gov. Cross-sectional Area (thickness) Investigate the factors affecting the resistance of a circuit. MDR-1, which encodes the P-GP transporter, multi-drug resistance proteins (MRPs), and the BC resistance protein (BCRP), which transport both hydrophilic and hydrophobic substrates, are particularly important for chemotherapy.111 Over 80% of the currently used anticancer agents are transported by P-GP, and thus its overexpression can lead to multi-drug resistance.113 Several reports have identified miRNAs that play important functions in BC (Table 2). The moving (C) The enzyme system involved in the deactivation of anti-cancer drugs, and therefore involved in the process of drug resistance, includes multi-drug resistance gene (MDR1) and glutathione S transferase Pi (GSTP1). Several miRNAs have been identified as biomarkers for prognosis and treatment planning in BC.139 miRNAs also play a crucial role in the regulation of BC cell sensitivity to chemotherapy.140,141 For example, miR326 and miR-451 negatively regulate the expression of MDR genes, including MDR-1, to overcome resistance. Resistance and Overcoming Resistance in Breast doi:10.1038/s41572-019-0111-2 National Library of Medicine In general, conventional therapeutic treatments for the management of BC patients include endocrine therapy, targeted therapy, and chemotherapy. PMC Recent development of targeted approaches for the treatment of breast cancer. Breast cancer. Mechanism of action of agents used in the treatment of BC. The development of molecular techniques, such as RNA sequencing, has allowed the determination of gene expression profiles, identification of tumor heterogeneity, and molecular classification of BC. The therapeutic decision for the management of patients with BC is based not only on the assessment of prognostic factors but also on the evaluation of clinical and pathological parameters. New therapeutic options are currently being developed for this disease, including ECT, androgen antagonists such as bicalutamide and abiraterone acetate,105 and nanosomal docetaxel lipid suspension (NDLS)based chemotherapy.106, Despite the associated short- and long-term risks, chemotherapy remains essential to prevent recurrence in many patients with advanced BC. Parisot JP, Hu XF, DeLuise M, Zalcberg JR. Altered expression of the IGF-1 receptor in a tamoxifen-resistant human breast cancer cell line, HER-2/neu and p53 expression versus tamoxifen resistance in estrogen receptorpositive, node-positive breast cancer, The role of HER2 in cancer therapy and targeted drug delivery. National Library of Medicine I searched for this question on the internet but didn't got a satisfactory explanation. Quandt D, Fiedler E, Boettcher D, Marsch WC, Seliger B. B7-h4 expression in human melanoma: its association with patients survival and antitumor immune response, Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer, Pertuzumab in the treatment of HER2-positive breast cancer: an evidence-based review of its safety, efficacy, and place in therapy, A new anti-HER2 antibody that enhances the anti-tumor efficacy of trastuzumab and pertuzumab with a distinct mechanism of action, The impact of PI3K inhibitors on breast cancer cell and its tumor microenvironment, Luminal-B breast cancer and novel therapeutic targets, Recent advances in the treatment of breast cancer, Trastuzumab emtansine: mechanisms of action and drug resistance, Trastuzumab deruxtecan in previously treated HER2-positive breast cancer, QTc prolongation in patients treated with trastuzumab and ado-trastuzumab-emtazine, Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer, Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-low expressing breast cancer: updated results of a large phase 1 study. Patients with triple-negative tumors receive mainly chemotherapy.24.
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