Dominant mechanisms of primary resistance differ from dominant mechanisms of secondary resistance to targeted therapies

Asić, Ksenija

doi:10.1016/j.critrevonc.2015.08.004

Cited by 31 publications

(35 citation statements)

References 245 publications

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“…Our data showed that NCI-N87-TraRT was more resistant to trastuzumab than NCI-N87 cell line, both in vitro and in vivo (Figure 1A, 1B). As tyrosine kinase receptors, which are ErbB2-like or partners of ErbB2, and some key molecules involving with ErbB2 signaling were reported to be upregulated in trastuzumab-resistant cancer cells [13–17], western blot was used to examine the level of EGFR, HER3, IGF1, AKT and ERK in H2-18-treated NCI-N87 and NCI-N87-TraRT cells. Compared with NCI-N87 cells, the phosphorylation of EGFR and ErbB3 were upregulated in NCI-N87-TraRT cells (Figure 1C).…”

Section: Resultsmentioning

confidence: 99%

“…The potential mechanisms underlying trastuzumab resistance have been widely studied, including mechanisms dependent on ErbB2 receptor activity and those independent of ErbB2 receptor activity [13, 14]. Mechanisms that are dependent on ErbB2 receptor activity includes overexpression of proteins that masks ErbB2 receptor, upregulation of target-like tyrosine kinase receptors or their ligands, and formation of truncated ErbB2 [13, 14].…”

Section: Discussionmentioning

confidence: 99%

“…Mechanisms that are dependent on ErbB2 receptor activity includes overexpression of proteins that masks ErbB2 receptor, upregulation of target-like tyrosine kinase receptors or their ligands, and formation of truncated ErbB2 [13, 14]. In contrast, mechanisms independent of ErbB2 receptor activity covers alterations of downstream components in PI3K/Akt signaling pathway, cell reprogramming by deregulation of anti-apoptotic proteins or cell cycle regulators, and EMT transition [13, 14]. Difference indeed exists between instinct and acquired resistance mechanisms [13].…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, mechanisms independent of ErbB2 receptor activity covers alterations of downstream components in PI3K/Akt signaling pathway, cell reprogramming by deregulation of anti-apoptotic proteins or cell cycle regulators, and EMT transition [13, 14]. Difference indeed exists between instinct and acquired resistance mechanisms [13]. Up to 70% of intrinsic resistance mechanisms do not overlap with acquired resistance mechanisms [18].…”

Section: Discussionmentioning

confidence: 99%

“…The dominant mechanisms of intrinsic resistance are independent of ErbB2 receptor activity, relating to inactive ErbB2 receptor and aberrations located in downstream signals [13]. The predominant resistance-generating alterations were PI3KCA mutation and loss of PTEN, which lead to persistent activation of PI3K/AKT signaling pathway [14, 18–21].…”

Section: Discussionmentioning

confidence: 99%

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Combating acquired resistance to trastuzumab by an anti-ErbB2 fully human antibody

Wang

et al. 2017

Oncotarget

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Trastuzumab resistance is a common problem that impedes the effectiveness of trastuzumab in ErbB2-amplified cancers. About 70% of ErbB2-amplified breast cancers do not respond to trastuzumab (de novo resistance), and the majority of the trastuzumab-responsive cancers progress within 1 year (acquired resistance). Different mechanisms exist between de novo and acquired resistance. Innate resistance mechanisms are mainly independent of ErbB2 receptor activity, and acquired resistance involves with alterations depending on ErbB2 activity. We previously reported H2-18, an ErbB2 domain I-specific antibody, which could circumvent de novo resistance to trastuzumab. Here, we modeled the development of acquired resistance by treating human gastric cancer cell line NCI-N87 with trastuzumab to obtain the trastuzumab-resistant subline, NCI-N87-TraRT. Next, we investigated the antitumor efficacy of H2-18 in NCI-N87-TraRT cell line. H2-18 exhibited a significantly greater antitumor activity in NCI-N87-TraRT tumor-bearing nude mice than pertuzumab and trastuzumab, either alone or in combination. The unique ability of H2-18 to overcome acquired resistance may be attributable to its potent programmed cell death-inducing activity, which was probably mediated by RIP1-ROS-JNK-c-Jun pathway. In conclusion, H2-18 may have the potential as an effective agent to circumvent acquired resistance to trastuzumab in ErbB2-overexpressing cancers.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Combating acquired resistance to trastuzumab by an anti-ErbB2 fully human antibody

Wang

et al. 2017

Oncotarget

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Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights

Zheng

Kros

2017

Medicinal Research Reviews

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To date, five cancer treatment modalities have been defined. The three traditional modalities of cancer treatment are surgery, radiotherapy, and conventional chemotherapy, and the two modern modalities include molecularly targeted therapy (the fourth modality) and immunotherapy (the fifth modality). The cardiotoxicity associated with conventional chemotherapy and radiotherapy is well known. Similar adverse cardiac events are resurging with the fourth modality. Aside from the conventional and newer targeted agents, even the most newly developed, immune‐based therapeutic modalities of anticancer treatment (the fifth modality), e.g., immune checkpoint inhibitors and chimeric antigen receptor (CAR) T‐cell therapy, have unfortunately led to potentially lethal cardiotoxicity in patients. Cardiac complications represent unresolved and potentially life‐threatening conditions in cancer survivors, while effective clinical management remains quite challenging. As a consequence, morbidity and mortality related to cardiac complications now threaten to offset some favorable benefits of modern cancer treatments in cancer‐related survival, regardless of the oncologic prognosis. This review focuses on identifying critical research‐practice gaps, addressing real‐world challenges and pinpointing real‐time insights in general terms under the context of clinical cardiotoxicity induced by the fourth and fifth modalities of cancer treatment. The information ranges from basic science to clinical management in the field of cardio‐oncology and crosses the interface between oncology and onco‐pharmacology. The complexity of the ongoing clinical problem is addressed at different levels. A better understanding of these research‐practice gaps may advance research initiatives on the development of mechanism‐based diagnoses and treatments for the effective clinical management of cardiotoxicity.

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Monitoring treatment efficacy and resistance in breast cancer patients via circulating tumor DNA genomic profiling

Chen

Sun²,

Yang

et al. 2019

Molec Gen & Gen Med

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Background: One of the major challenges in managing invasive breast cancer (BC) is the lack of reliable biomarkers to track response. Circulating tumor DNA (ctDNA) from liquid biopsy, as a candidate biomarker, provides a valuable assessment of BC patients. In this retrospective study, we evaluated the utility of ctDNA to reflect the efficacy of treatment and to monitor resistance mechanisms. Methods: Targeted next-generation sequencing (NGS) of 416 cancer-relevant genes was performed on 41 plasma biopsy samples of 19 HER2+ and 12 HER2-BC patients. Longitudinal ctDNA samples were analyzed in three BC patients over the treatment course for detecting acquired mutations. Results: In HER2+ BC patients, ERBB2 somatic copy numbers in ctDNA samples were significantly higher in patients progressed on HER2-targeted therapy than those who were still responding to the treatment. Recurrent acquired mutations were detected in genes including ERBB2, TP53, EGFR, NF1, and SETD2, which may contribute to trastuzumab resistance. In longitudinal analyses, the observed mutation allele frequencies were tracked closely in concordance with treatment responses. A novel ERBB2 p.(Leu869Arg) mutation was acquired in one patient upon resistant to trastuzumab therapy, which was further validated as an oncogenic mutation in vitro and contributed to resistance. In HER2-BC patients with chemotherapy resistance, genetic alterations on TP53, PIK3CA, and DNA damage repair genes were frequently observed. Conclusions: In summary, ctDNA monitoring, particularly longitudinal analyses, provides valuable insights into the assessment of targeted therapy efficacy and gene alterations underlying trastuzumab resistance and chemotherapy resistance in HER2+ and HER2-BC patients, respectively. K E Y W O R D Sbreast cancer, chemotherapy, ctDNA, drug resistance, ERBB2, trastuzumab 2 of 11 | CHEN Et al.

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Dominant mechanisms of primary resistance differ from dominant mechanisms of secondary resistance to targeted therapies

Cited by 31 publications

References 245 publications

Combating acquired resistance to trastuzumab by an anti-ErbB2 fully human antibody

Combating acquired resistance to trastuzumab by an anti-ErbB2 fully human antibody

Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights

Monitoring treatment efficacy and resistance in breast cancer patients via circulating tumor DNA genomic profiling

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