scholarly journals The C-terminal HSP90 inhibitor NCT-58 kills trastuzumab-resistant breast cancer stem-like cells

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Soeun Park ◽  
Yoon-Jae Kim ◽  
Jung Min Park ◽  
Minsu Park ◽  
Kee Dal Nam ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Xenograft Model ◽  
Hsp90 Inhibitor ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Her Family ◽  
Akt Phosphorylation ◽  
Anti Tumor Activity ◽  
Target Effects ◽  
Positive Breast Cancer

AbstractN-terminal HSP90 inhibitors in development have had issues arising from heat shock response (HSR) induction and off-target effects. We sought to investigate the capacity of NCT-58, a rationally-synthesized C-terminal HSP90 inhibitor, to kill trastuzumab-resistant HER2-positive breast cancer stem-like cells. NCT-58 does not induce the HSR due to its targeting of the C-terminal region and elicits anti-tumor activity via the simultaneous downregulation of HER family members as well as inhibition of Akt phosphorylation. NCT-58 kills the rapidly proliferating bulk tumor cells as well as the breast cancer stem-like population, coinciding with significant reductions in stem/progenitor markers and pluripotent transcription factors. NCT-58 treatment suppressed growth and angiogenesis in a trastuzumab-resistant xenograft model, concomitant with downregulation of ICD-HER2 and HSF-1/HSP70/HSP90. These findings warrant further investigation of NCT-58 to address trastuzumab resistance in heterogeneous HER2-positive cancers.

scholarly journals A novel HSP90 inhibitor targeting the C-terminal domain attenuates trastuzumab resistance in HER2-positive breast cancer

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Jung Min Park ◽  
Yoon-Jae Kim ◽  
Soeun Park ◽  
Minsu Park ◽  
Lee Farrand ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hsp90 Inhibitor ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Mammosphere Formation ◽  
Her2 Positive Breast Cancer ◽  
Induced Apoptosis ◽  
Positive Breast Cancer

AbstractTrastuzumab resistance in HER2-positive breast cancer is associated with a poorer prognosis. HSP90 is thought to play a major role in such resistance, but N-terminal inhibitors of this target have had little success. We sought to investigate the utility of NCT-547, a novel, rationally-designed C-terminal HSP90 inhibitor in the context of overcoming trastuzumab resistance. NCT-547 treatment significantly induced apoptosis without triggering the heat shock response (HSR), accompanied by caspase-3/− 7 activation in both trastuzumab-sensitive and -resistant cells. NCT-547 effectively promoted the degradation of full-length HER2 and truncated p95HER2, while also attenuating hetero-dimerization of HER2 family members. The impairment of cancer stem-like traits was observed with reductions in ALDH1 activity, the CD24low/CD44high subpopulation, and mammosphere formation in vitro and in vivo. NCT-547 was an effective inhibitor of tumor growth and angiogenesis, and no toxic outcomes were found in initial hepatic and renal analysis. Our findings suggest that NCT-547 may have applications in addressing trastuzumab resistance in HER2-positive breast cancer.

scholarly journals Autocrine CCL5 effect mediates trastuzumab resistance by ERK pathway activation in HER2-positive breast cancer

2020 ◽  
pp. molcanther.1172.2019 ◽  
Author(s):  
Sandra Zazo ◽  
Paula González-Alonso ◽  
Ester Martin-Aparicio ◽  
Cristina Chamizo ◽  
Melani Luque ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Erk Pathway ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Pathway Activation ◽  
Positive Breast Cancer

scholarly journals Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Maria Gaibar ◽  
Laura Beltrán ◽  
Alicia Romero-Lorca ◽  
Ana Fernández-Santander ◽  
Apolonia Novillo
Keyword(s):  
Breast Cancer ◽  
Somatic Mutations ◽  
Tyrosine Kinase Domain ◽  
Her2 Overexpression ◽  
Breast Cancer Patients ◽  
Trastuzumab Resistance ◽  
Her2 Gene ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. These carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive phenotype and a lower rate of disease-free and overall survival. Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. Some authors have attributed somatic mutations in HER2, a role in resistance to anti-HER2 therapy as differential regulation of HER2 has been observed among patients. Recently, studies in metastatic ER + tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy. In an effort to identify possible biomarkers of the efficacy of anti-HER2 therapy, we here review the known single-nucleotide polymorphisms (SNPs) of the HER2 gene found in HER2-positive breast cancer patients and their relationship with clinical outcomes. Information was recompiled on 11 somatic HER2 SNPs. Seven polymorphisms are located in the tyrosine kinase domain region of the gene contrasting with the low number of mutations found in extracellular and transmembrane areas. HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments. Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib. By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from trastuzumab. Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I. These data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer.

scholarly journals Transcriptome-wide identification of mRNAs and lincRNAs associated with trastuzumab-resistance in HER2-positive breast cancer

Oncotarget ◽  
2016 ◽  
Vol 7 (33) ◽  
pp. 53230-53244 ◽  
Author(s):  
Callie R. Merry ◽  
Sarah McMahon ◽  
Megan E. Forrest ◽  
Cynthia F. Bartels ◽  
Alina Saiakhova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

scholarly journals ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer

Oncotarget ◽  
2014 ◽  
Vol 5 (16) ◽  
pp. 6633-6646 ◽  
Author(s):  
Katharina Feldinger ◽  
Daniele Generali ◽  
Gabriela Kramer-Marek ◽  
Merel Gijsen ◽  
Tzi Bun Ng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer
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