scholarly journals Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jennifer Y. Ge ◽  
Shaokun Shu ◽  
Mijung Kwon ◽  
Bojana Jovanović ◽  
Katherine Murphy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Acquired Resistance

scholarly journals Diverse Roles of Annexin A6 in Triple-Negative Breast Cancer Diagnosis, Prognosis and EGFR-Targeted Therapies

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1855 ◽  
Author(s):  
Olga Y. Korolkova ◽  
Sarrah E. Widatalla ◽  
Stephen D. Williams ◽  
Diva S. Whalen ◽  
Heather K. Beasley ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Triple Negative Breast Cancer ◽  
Kinase Inhibitors ◽  
Triple Negative ◽  
Acquired Resistance ◽  
Breast Cancer Diagnosis ◽  
Scaffolding Protein ◽  
Poor Overall Survival ◽  
Suppressor Activity

The calcium (Ca2+)-dependent membrane-binding Annexin A6 (AnxA6), is a multifunctional, predominantly intracellular scaffolding protein, now known to play relevant roles in different cancer types through diverse, often cell-type-specific mechanisms. AnxA6 is differentially expressed in various stages/subtypes of several cancers, and its expression in certain tumor cells is also induced by a variety of pharmacological drugs. Together with the secretion of AnxA6 as a component of extracellular vesicles, this suggests that AnxA6 mediates distinct tumor progression patterns via extracellular and/or intracellular activities. Although it lacks enzymatic activity, some of the AnxA6-mediated functions involving membrane, nucleotide and cholesterol binding as well as the scaffolding of specific proteins or multifactorial protein complexes, suggest its potential utility in the diagnosis, prognosis and therapeutic strategies for various cancers. In breast cancer, the low AnxA6 expression levels in the more aggressive basal-like triple-negative breast cancer (TNBC) subtype correlate with its tumor suppressor activity and the poor overall survival of basal-like TNBC patients. In this review, we highlight the potential tumor suppressor function of AnxA6 in TNBC progression and metastasis, the relevance of AnxA6 in the diagnosis and prognosis of several cancers and discuss the concept of therapy-induced expression of AnxA6 as a novel mechanism for acquired resistance of TNBC to tyrosine kinase inhibitors.

scholarly journals Lapatinib-induced annexin A6 upregulation as an adaptive response of triple-negative breast cancer cells to EGFR tyrosine kinase inhibitors

2018 ◽  
Vol 40 (8) ◽  
pp. 998-1009 ◽  
Author(s):  
Sarrah E Widatalla ◽  
Olga Y Korolkova ◽  
Diva S Whalen ◽  
J Shawn Goodwin ◽  
Kevin P Williams ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Triple Negative Breast Cancer ◽  
Plasma Membranes ◽  
Kinase Inhibitors ◽  
Triple Negative ◽  
Acquired Resistance ◽  
Cholesterol Depletion ◽  
Late Endosomes

Abstract The epidermal growth factor receptor (EGFR) is a major oncogene in triple-negative breast cancer (TNBC), but the use of EGFR-targeted tyrosine kinase inhibitors (TKI) and therapeutic monoclonal antibodies is associated with poor response and acquired resistance. Understanding the basis for the acquired resistance to these drugs and identifying biomarkers to monitor the ensuing resistance remain a major challenge. We previously showed that reduced expression of annexin A6 (AnxA6), a calcium-dependent membrane-binding tumor suppressor, not only promoted the internalization and degradation of activated EGFR but also sensitized TNBC cells to EGFR-TKIs. Here, we demonstrate that prolong (>3 days) treatment of AnxA6-low TNBC cells with lapatinib led to AnxA6 upregulation and accumulation of cholesterol in late endosomes. Basal extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation was EGFR independent and significantly higher in lapatinib-resistant MDA-MB-468 (LAP-R) cells. These cells were more sensitive to cholesterol depletion than untreated control cells. Inhibition of lapatinib-induced upregulation of AnxA6 by RNA interference (A6sh) or withdrawal lapatinib from LAP-R cells not only reversed the accumulation of cholesterol in late endosomes but also led to enrichment of plasma membranes with cholesterol, restored EGFR-dependent activation of ERK1/2 and sensitized the cells to lapatinib. These data suggest that lapatinib-induced AnxA6 expression and accumulation of cholesterol in late endosomes constitute an adaptive mechanism for EGFR-expressing TNBC cells to overcome prolong treatment with EGFR-targeted TKIs and can be exploited as an option to inhibit and/or monitor the frequently observed acquired resistance to these drugs.

Abstract 4117: Mechanisms of acquired resistance to c-Src kinase inhibitor in triple negative breast cancer

2017 ◽  
Author(s):  
Rabia A. Gilani ◽  
Eric J. Lachacz ◽  
Sameer Phadke ◽  
Li Wei Bao ◽  
Xu Cheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Src Kinase

scholarly journals Overcoming acquired resistance to HSP90 inhibition by targeting JAK-STAT signalling in triple-negative breast cancer

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Nuramalina H. Mumin ◽  
Neele Drobnitzky ◽  
Agata Patel ◽  
Luiza Madia Lourenco ◽  
Fiona F. Cahill ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Acquired Resistance ◽  
Hsp90 Inhibition

Targeting Different Pathways Using Novel Combination Therapy in Triple Negative Breast Cancer

2020 ◽  
Vol 20 (8) ◽  
pp. 586-602
Author(s):  
Manzoor A. Mir ◽  
Hina Qayoom ◽  
Umar Mehraj ◽  
Safura Nisar ◽  
Basharat Bhat ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Combination Therapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Single Agent ◽  
Acquired Resistance ◽  
Pi3k Pathway ◽  
Chemotherapeutic Agents ◽  
High Grade ◽  
Efficient Treatment

Triple negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer accounting for 15-20% of cases and is defined by the lack of hormonal receptors viz., estrogen receptor (ER), progesterone receptor (PR) and expression of human epidermal growth receptor 2 (HER2). Treatment of TNBC is more challenging than other subtypes of breast cancer due to the lack of markers for the molecularly targeted therapies (ER, PR, and HER-2/ Neu), the conventional chemotherapeutic agents are still the mainstay of the therapeutic protocols of its patients. Despite, TNBC being more chemo-responsive than other subtypes, unfortunately, the initial good response to the chemotherapy eventually turns into a refractory drug-resistance. Using a monotherapy for the treatment of cancer, especially high-grade tumors like TNBC, is mostly worthless due to the inherent genetic instability of tumor cells to develop intrinsic and acquired resistance. Thus, a cocktail of two or more drugs with different mechanisms of action is more effective and could successfully control the disease. Furthermore, combination therapy reveals more, or at least the same, effectiveness with lower doses of every single agent and decreases the likelihood of chemoresistance. Herein, we shed light on the novel combinatorial approaches targeting PARP, EGFR, PI3K pathway, AR, and wnt signaling, HDAC, MEK pathway for efficient treatment of high-grade tumors like TNBC and decreasing the onset of resistance.

scholarly journals Impact of the Pd2Spm (Spermine) Complex on the Metabolism of Triple-Negative Breast Cancer Tumors of a Xenograft Mouse Model

2021 ◽  
Vol 22 (19) ◽  
pp. 10775
Author(s):  
Tatiana J. Carneiro ◽  
Rita Araújo ◽  
Martin Vojtek ◽  
Salomé Gonçalves-Monteiro ◽  
Ana L. M. Batista de Carvalho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mouse Model ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Acquired Resistance ◽  
Palladium Complexes ◽  
Breast Cancer Cell Lines ◽  
Reference Drug ◽  
Xenograft Mouse Model

The interest in palladium(II) compounds as potential new anticancer drugs has increased in recent years, due to their high toxicity and acquired resistance to platinum(II)-derived agents, namely cisplatin. In fact, palladium complexes with biogenic polyamines (e.g., spermine, Pd2Spm) have been known to display favorable antineoplastic properties against distinct human breast cancer cell lines. This study describes the in vivo response of triple-negative breast cancer (TNBC) tumors to the Pd2Spm complex or to cisplatin (reference drug), compared to tumors in vehicle-treated mice. Both polar and lipophilic extracts of tumors, excised from a MDA-MB-231 cell-derived xenograft mouse model, were characterized through nuclear magnetic resonance (NMR) metabolomics. Interestingly, the results show that polar and lipophilic metabolomes clearly exhibit distinct responses for each drug, with polar metabolites showing a stronger impact of the Pd(II)-complex compared to cisplatin, whereas neither drug was observed to significantly affect tumor lipophilic metabolism. Compared to cisplatin, exposure to Pd2Spm triggered a higher number of, and more marked, variations in some amino acids, nucleotides and derivatives, membrane precursors (choline and phosphoethanolamine), dimethylamine, fumarate and guanidine acetate, a signature that may be relatable to the cytotoxicity and/or mechanism of action of the palladium complex. Putative explanatory biochemical hypotheses are advanced on the role of the new Pd2Spm complex in TNBC metabolism.

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