Apatinib exhibits synergistic effect with pyrotinib and reverses acquired pyrotinib resistance in HER2-positive gastric
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ORIGINAL ARTICLE
Apatinib exhibits synergistic effect with pyrotinib and reverses acquired pyrotinib resistance in HER2‑positive gastric cancer via stem cell factor/c‑kit signaling and its downstream pathways Beibei Su1 · Tingting Huang1 · Yu Jin1 · Han Yin1 · Hong Qiu1 · Xianglin Yuan1 Received: 17 May 2020 / Accepted: 18 September 2020 © The Author(s) 2020
Abstract Background Recently, progress has been made in the development of targeted therapies for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). However, drug resistance has severely limited the efficacy of anti-HER2 therapies. Pyrotinib is a novel pan-HER inhibitor. Although it is effective in HER2-positive GC treatment, its efficacy in combination with apatinib and associated resistance mechanisms in HER2-positive GC remains unclear. Methods In this study, the combination effects of pyrotinib and apatinib were examined in two pyrotinib-sensitive GC cells and xenografts. The RNA sequencing was used to determine the underlying mechanisms of acquired pyrotinib resistance. The role of imatinib and apatinib in reversing pyrotinib resistance was tested in pyrotinib-resistant cells and xenografts. Results Here, we reported that a combination of pyrotinib and apatinib exhibits synergistic effect in HER2-positive NCIN87 xenografts, and showed enhanced antitumor efficacy in HER2-positive GC, both in vitro and in vivo. Moreover, up-regulation of the stem cell factor (SCF) levels, and the PI3K/AKT and MAPK pathways was associated with acquired pyrotinib resistance in HER2-positive GC. Mechanistically, we demonstrated that the activation of the SCF/c-kit signaling and its downstream PI3K/AKT and MAPK pathways mediated pyrotinib resistance by promoting cell survival and proliferation. Imatinib and apatinib augmented the sensitivity of pyrotinib-resistant cells and xenografts to pyrotinib, by blocking SCF/c-kit signaling. Conclusion These results highlight the effectiveness of pyrotinib combined with apatinib in HER2-positive GC and acquired pyrotinib resistance, thus providing a theoretical basis for new treatment methods. Keywords Pyrotinib · Gastric cancer · HER2 · Apatinib · Pyrotinib resistance
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10120-020-01126-9) contains supplementary material, which is available to authorized users.
Rapid progress in genomic analysis and sequencing technology has opened doors to a new era of precision treatment, and targeted therapy has become one of the most important treatment regimens for cancer. Gastric cancer (GC) ranks third among the leading causes of cancer deaths worldwide; however, targeted therapies for GC are very limited [1].
* Xianglin Yuan [email protected]
Han Yin [email protected]
Beibei Su [email protected]
Hong Qiu [email protected]
Tingting Huang [email protected]
1
Yu Jin [email protected]
Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and T
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