Dataset Information

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.

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 NCI-N87 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.

SUBMITTER: Su B

PROVIDER: S-EPMC7902570 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

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.

Su Beibei B Huang Tingting T Jin Yu Y Yin Han H Qiu Hong H Yuan Xianglin X

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 20201008 2

<h4>Background</h4>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.<h4>Methods</h4>In this study, ...[more]

PMID: 33030616

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Project description:AimPyrotinib (an irreversible pan-ErbB small-molecular tyrosine kinase inhibitor) was approved in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and showed great antitumor activity in preclinical studies of gastric cancer (GC). This study was first designed to prospectively assess pyrotinib in pretreated HER2-positive GC.MethodsThis multicenter, phase I study followed a standard "3 + 3" design and included two parts. In the pyrotinib part, pyrotinib was administered orally, once per day at dose levels of 240, 320, 400, and 480 mg. In the pyrotinib plus docetaxel part, patients received pyrotinib (qd, d1-21, q3W) combined with docetaxel (60 mg/m2 , d1, q3W) at dose levels of 240, 320, and 400 mg. Primary endpoints were to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of pyrotinib as monotherapy or coadministered with docetaxel.ResultsA total of 25 patients were enrolled and received pyrotinib (n = 15) or pyrotinib plus docetaxel (n = 10). One DLT was observed in pyrotinib monotherapy part (Grade 3 uncontrolled diarrhea after supportive care) and pyrotinib plus docetaxel part (Grade 4 neutropenia and leukopenia). In the pyrotinib monotherapy part, MTD was not reached. Diarrhea, anemia, neutropenia, and leukopenia were the most common treatment-related adverse events (TRAEs). The RP2D for pyrotinib monotherapy was recommended as 400 mg. After combining with docetaxel, the risk of leukopenia and neutropenia was increased. Grade ≥3 TRAEs were reported for four patients in the monotherapy part and for eight patients in the combination part. Mean t1/2 was approximately 20 h. Pyrotinib exposure was dose-dependent with a nonlinear relationship versus dose. There were five patients who had confirmed partial response (monotherapy: one each at 240, 400, and 480 mg dose cohort; combination therapy: two at 240 mg dose cohort), resulting in an objective response rate of 21% and 20%, respectively.ConclusionsPyrotinib alone and combined with docetaxel showed acceptable toxicities in patients with pretreated HER2-positive GC.Trial registrationThis study was registered with ClinicalTrials.gov, NCT02378389.

Dataset Information

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.

Background

Methods

Results

Conclusion

Publications

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.

Similar Datasets

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