Abstract 1079: A synthetic lethal strategy using PARP and ATM inhibition for overcoming trastuzumab-resistance in HER2-positive cancers

2021 ◽  
Author(s):  
Kyoung-Seok Oh ◽  
Ah-Rong Nam ◽  
Ju-Hee Bang ◽  
Hye-Rim Seo ◽  
Jae-Min Kim ◽  
...  
Keyword(s):  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Synthetic Lethal

scholarly journals Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 400 ◽  
Author(s):  
Seiichiro Mitani ◽  
Hisato Kawakami
Keyword(s):  
Gastroesophageal Junction ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Drug Conjugates ◽  
Gastroesophageal Junction Cancer ◽  
Development Of Resistance ◽  
Epidermal Growth ◽  
Antibody Drug

Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody–drug conjugates that are under development and have shown promising antitumor activity in early studies.

scholarly journals Targeting the PI3K and MAPK pathways to improve response to HER2-targeted therapies in HER2-positive gastric cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
M. Janusz Mezynski ◽  
Angela M. Farrelly ◽  
Mattia Cremona ◽  
Aoife Carr ◽  
Clare Morgan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Lines ◽  
Somatic Mutations ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Erbb Family ◽  
Gastric Tumour ◽  
Pi3k Signalling ◽  
Trial Setting

Abstract Background Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear. Methods Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies. Results Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM–1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05). Conclusions PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.

scholarly journals Reactive stroma and trastuzumab resistance in HER2‐positive early breast cancer

2020 ◽  
Vol 147 (1) ◽  
pp. 266-276 ◽  
Author(s):  
Amir Sonnenblick ◽  
Mali Salmon‐Divon ◽  
Roberto Salgado ◽  
Efrat Dvash ◽  
Noam Pondé ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Breast Cancer ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Reactive Stroma

Abstract 2110: WEE1 inhibition could reverse trastuzumab resistance by downregulation of PD-L1 in HER2-positive cancers

2019 ◽  
Author(s):  
Meihua Jin ◽  
Ah-Rong Nam ◽  
Ji-Eun Park ◽  
Ju-Hee Bang ◽  
Kyoung-Seok Oh ◽  
...  
Keyword(s):  
Trastuzumab Resistance ◽  
Her2 Positive

Abstract P4-10-16: Reactive stroma and trastuzumab resistance in HER2-positive early breast cancer

2020 ◽  
Author(s):  
Amir Sonnenblick ◽  
Mali Salmon-Divon ◽  
Roberto Salgado ◽  
Noam Pondé ◽  
Sibylle Loibl ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Breast Cancer ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Reactive Stroma

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 NCAPG confers trastuzumab resistance via activating SRC/STAT3 signaling pathway in HER2-positive breast cancer

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Lili Jiang ◽  
Liangliang Ren ◽  
Han Chen ◽  
Jinyuan Pan ◽  
Zhuojun Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Recurrence ◽  
Early Recurrence ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Her2 Breast Cancer ◽  
Structural Maintenance Of Chromosome ◽  
Underlying Mechanisms

AbstractHER2+ breast cancer (BC) is characterized by rapid growth, early recurrence, early metastasis, and chemoresistance. Trastuzumab is the most effective treatment for HER2+ BC and effectively reduces the risk of recurrence and death of patients. Resistance to trastuzumab results in cancer recurrence and metastasis, leading to poor prognosis of HER2+ BC. In the present study, we found that non-structural maintenance of chromosome condensin 1 complex subunit G (NCAPG) expression was highly upregulated in trastuzumab-resistant HER2+ BC. Ectopic NCAPG was positively correlated with tumor relapse and shorter survival in HER2+ BC patients. Moreover, overexpression of NCAPG promoted, while silencing of NCAPG reduced, the proliferative and anti-apoptotic capacity of HER2+ BC cells both in vitro and in vivo, indicating NCAPG reduces the sensitivity of HER2+ BC cells to trastuzumab and may confer trastuzumab resistance. Furthermore, our results suggest that NCAPG triggers a series of biological cascades by phosphorylating SRC and enhancing nuclear localization and activation of STAT3. To summarize, our study explores a crucial role for NCAPG in trastuzumab resistance and its underlying mechanisms in HER2+ BC, and suggests that NCAPG could be both a potential prognostic marker as well as a therapeutic target to effectively overcome trastuzumab resistance.

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.

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