Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo

Schwab, Carlton L.; English, Diana P.; Roque, Dana M.; Bellone, Stefania; Lopez, Salvatore; Cocco, Emiliano; Nicoletti, Roberta; Rutherford, Thomas J.; Schwartz, Peter E.; Santin, Alessandro D.

doi:10.1016/j.ygyno.2014.08.006

Cited by 30 publications

(24 citation statements)

References 29 publications

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“…Cancers that overexpress HER2 have been linked with worse prognosis when compared with matched HER2 non-amplified ones, including a higher mortality rate in early stages of the disease, reduced relapse time, and a higher incidence of metastases [50,51]. Trastuzumab emtansine (T-DM1, Kadcyla™, Genentech, South San Francisco, CA, USA) is a new HER2-targeting immunotoxin which was developed through a combination of Trastuzumab (T) (Herceptin, Genentech, South San Francisco, CA, USA) with maytansinoid cytotoxin (DM1), which significantly inhibits the polarization of microtubules (Figure 1) [52]. For this reason, T-DM1 binds the extracellular sub-domain IV of the HER2 receptor after internalization.…”

Section: Resultsmentioning

confidence: 99%

Target Therapies for Uterine Carcinosarcomas: Current Evidence and Future Perspectives

Vitale

Laganà

Capriglione

et al. 2017

IJMS

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Carcinosarcomas (CS) in gynecology are very infrequent and represent only 2–5% of uterine cancers. Despite surgical cytoreduction and subsequent chemotherapy being the primary treatment for uterine CS, the overall five-year survival rate is 30 ± 9% and recurrence is extremely common (50–80%). Due to the poor prognosis of CS, new strategies have been developed in the last few decades, targeting known dysfunctional molecular pathways for immunotherapy. In this paper, we aimed to gather the available evidence on the latest therapies for the treatment of CS. We performed a systematic review using the terms “uterine carcinosarcoma”, “uterine Malignant Mixed Müllerian Tumors”, “target therapies”, “angiogenesis therapy”, “cancer stem cell therapy”, “prognostic biomarker”, and “novel antibody-drug”. Based on our results, the differential expression and accessibility of epithelial cell adhesion molecule-1 on metastatic/chemotherapy-resistant CS cells in comparison to normal tissues and Human Epidermal Growth Factor Receptor 2 (HER2) open up new possibilities in the field of target therapy. Nevertheless, future investigations are needed to clarify the impact of these new therapies on survival rate and medium-/long-term outcomes.

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Section: Resultsmentioning

confidence: 99%

Target Therapies for Uterine Carcinosarcomas: Current Evidence and Future Perspectives

Vitale

Laganà

Capriglione

et al. 2017

IJMS

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“…The effect of single agent neratinib and taselisib on the viability of 3 primary USC cell lines (i.e., USPC-ARK-2, 20, 21) has been previously reported (23, 27). The effect of neratinib on the viability and IC 50 of USPC-ARK-1 cell line was determined in flow-cytometry based assays as previously described (23, 27).…”

Section: Methodsmentioning

confidence: 91%

Dual HER2/PIK3CA Targeting Overcomes Single-Agent Acquired Resistance in HER2-Amplified Uterine Serous Carcinoma Cell Lines In Vitro and In Vivo

Lopez

Cocco

Black

et al. 2015

Molecular Cancer Therapeutics

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HER2/neu gene amplification and PIK3CA driver mutations are common in uterine serous carcinoma (USC), and may represent ideal therapeutic targets against this aggressive variant of endometrial cancer. We examined the sensitivity to neratinib, taselisib and the combination of the two compounds in in vitro and in vivo experiments using PIK3CA mutated and PIK3CA-wild type HER2/neu amplified USC cell lines. Cell viability and cell cycle distribution were assessed using flow-cytometry assays. Downstream signaling was assessed by immunoblotting. Preclinical efficacy of single versus dual inhibition was evaluated in vivo using two USC-xenografts. We found both single agent neratinib and taselisib to be active but only transiently effective in controlling the in vivo growth of USC xenografts harboring HER2/neu gene amplification with or without oncogenic PIK3CA mutations. In contrast, the combination of the two inhibitors caused a stronger and long lasting growth inhibition in both USC xenografts when compared to single agent therapy. Combined targeting of HER2 and PIK3CA was associated with a significant and dose-dependent increase in the percentage of cells in the G0/G1 phase of the cell cycle and a dose-dependent decline in the phosphorylation of S6. Importantly, dual inhibition therapy initiated after tumor progression in single agent-treated mice was still remarkably effective at inducing tumor regression in both large PIK3CA or pan-ErbB inhibitor-resistant USC xenografts. Dual HER2/PIK3CA blockade may represent a novel therapeutic option for USC patients harboring tumors with HER2/neu gene amplification and mutated or wild type PIK3CA resistant to chemotherapy.

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“…Neratinib specifically targets a conserved cytosine residue in both ErbB1 and HER2, and covalently binds to this site through a Michael reaction allowing for less cytotoxic side effects than might be expected when using an irreversible inhibitor [17]. Previously published preclinical data in HER2/neu amplified uterine serous carcinoma suggest that neratinib may be a highly efficacious treatment modality in patients harboring chemotherapy resistant gynecologic malignancies that harbor HER2/neu amplification [10]. This study provides the first preclinical data regarding Neratinib’s potential efficacy in the treatment of HER2/neu amplified uterine and ovarian carcinosarcomas.…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that amplification or mutation of the ErbB pathways can lead to increased metabolic rate, proliferation and oncogenesis. Previously reported preclinical data in HER2/neu amplified uterine serous carcinoma suggests that targeting this pathway with the small tyrosine kinase inhibitor, neratinib, maybe an efficacious strategy in the treatment of highly aggressive gynecologic malignancies [10]. The amplification of HER2/neu has been reported to occur in 20–25% of uterine carcinosarcomas while the frequency of amplification in ovarian carcinosarcomas has not yet been reported [11].…”

Section: Introductionmentioning

confidence: 99%

Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo

Schwab

English

Black

et al. 2015

Gynecologic Oncology

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Objective Carcinosarcoma is a deadly gynecologic malignancy with few effective treatment options. The study of new therapies is difficult because of its rarity. The objective of this study was to determine the efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma. Methods The efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma was determined in vitro using seven primary carcinosarcoma cell lines with differential expression of HER2/neu. Data regarding IC50, cell cycle distribution, and cell signaling changes were assessed by flow cytometry. The efficacy of neratinib was determined in treating mice harboring HER2 amplified carcinosarcoma xenografts. Results Two of seven (28.5%) carcinosarcoma cell lines were HER2/neu amplified. HER2/neu amplified cell lines SARARK6 and SARARK9 were significantly more sensitive to neratinib than the five non-HER2/neu amplified carcinosarcoma cell lines (mean±SEM IC50: 0.014μM±0.004 vs. 0.164μM±0.019 p=0.0003). Neratinib treatment caused a significant build up in G0/G1 phase of the cell cycle, arrest auto phosphorylation of HER2/neu and activation of S6. Neratinib inhibited tumor growth (p=0.012) and prolonged survival in mice harboring HER2 amplified carcinosarcoma xenografts (p=0.0039). Conclusions Neratinib inhibits HER2 amplified carcinosarcoma proliferation, signaling, cell cycle progression and tumor growth in vitro. Neratinib inhibits HER2/neu amplified xenograft growth and improves overall survival. Clinical trials are warranted.

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Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo

Cited by 30 publications

References 29 publications

Target Therapies for Uterine Carcinosarcomas: Current Evidence and Future Perspectives

Target Therapies for Uterine Carcinosarcomas: Current Evidence and Future Perspectives

Dual HER2/PIK3CA Targeting Overcomes Single-Agent Acquired Resistance in HER2-Amplified Uterine Serous Carcinoma Cell Lines In Vitro and In Vivo

Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo

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