Radiosensitization of HER2-positive esophageal cancer cells by pyrotinib.
ABSTRACT: Radiation therapy is a widely used treatment for esophageal cancer. However, radiation resistance might result in a poor prognosis. Overexpression of HER2 has been related to adaptive radiation resistance. Pyrotinib is a HER2 inhibitor that shows an anti-tumor effect in breast cancer. The present study aims to explore the influence of pyrotinib combined with radiotherapy on HER2-positive esophageal cancer cells and explore the underlying mechanism. We screened two cell lines (TE-1 and KYSE30) that highly express HER2 from several human esophageal cancer cell lines. Cells were treated with pyrotinib or/and radiation. Cell proliferation, cell cycle distribution, and cell migration were measured. The protein levels involved in cell cycle and DNA repair were measured by Western blot. Results showed that pyrotinib inhibited HER2 activation and exerted an anti-proliferative effect in TE-1 and KYSE30 cells. Furthermore, it enhanced the anti-proliferative effect of radiation in these two cell lines. These effects might be via inhibiting HER2 phosphorylation, inducing G0/G1 arrest, and reducing EMT and DNA repair. Our results indicated that pyrotinib sensitivitied HER2 positive esophageal cancer cells to radiation treatment through various mechanisms. These findings may provide a new therapeutic strategy for treating HER2 positive esophageal cancer.
Project description:The overexpression or amplification of HER2 has been observed in a significant proportion of both gastric cancer (GC) and breast cancer (BC) cases. Pyrotinib is an irreversible dual (EGFR/HER2) tyrosine kinase inhibitor (TKI), newly evaluated for the treatment of HER2?overexpressing cancer types. As radiotherapy (RT) serves a crucial role in controlling the local recurrence of GC and BC, the present study investigated the impact of pyrotinib on the irradiation response. The current results demonstrated that pyrotinib enhanced the radiosensitivity of HER2?overexpressing GC and BC cells in vitro and in vivo. In both NCI?N87 and SKBR3 cells, pyrotinib suppressed the irradiation?induced HER2 nuclear transport. Furthermore, pyrotinib increased DNA damage induced by irradiation in both cancer cell lines. Pyrotinib also enhanced the cytotoxicity of docetaxel, which may provide a novel strategy for potential drug combinations. Thus, pyrotinib is a promising irradiation sensitizer in patients with HER2?overexpressing GC and BC. The present results provide a theoretical foundation for further clinical evaluation of pyrotinib.
Project description:BACKGROUND:Pyrotinib was well tolerated but its efficacy was unsatisfactory in patients with HER2-positive gastric cancer (GC) (NCT02378389). This study was to optimize the efficacy of pyrotinib. METHODS:Human GC cell lines and AVATAR mice were used to explore the refractory mechanisms of pyrotinib. A pyrotinib-combined strategy was proposed, which was validated in preclinical AVATAR mouse and in clinical patients enrolled in a phase I clinical trial (NCT03480256). RESULTS:Dysregulation of CCND1-CDK4/6-Rb axis might be the key to pyrotinib refractory. The strategy of pyrotinib combined with a CDK4/6 inhibitor SHR6390 was proposed and validated in preclinical AVATAR mouse, which was successfully verified in clinical patients. For five patients treated with pyrotinib plus SHR6390 who had available response evaluation, the best response was partial response in three patients, stable disease in one patient, and progressive disease in one patient. The progression-free survival times were 120, 200, 532, 109, and 57 days, respectively. CONCLUSIONS:This translational study suggests that pyrotinib combined with SHR6390 may serve as a promising strategy for patients with HER2-positive GC. TRIAL REGISTRATION:The ClinicalTrials.gov identifiers are NCT02378389 (https://clinicaltrials.gov/ct2/show/study/NCT02378389, registered in 11 February 2015) and NCT03480256 (https://clinicaltrials.gov/ct2/show/study/NCT03480256, registered in 8 March 2018).
Project description:BACKGROUND:Effective targeted therapy for non-small-cell lung cancer (NSCLC) patients with human epidermal growth factor receptor 2 (HER2) mutations remains an unmet need. This study investigated the antitumor effect of an irreversible pan-HER receptor tyrosine kinase inhibitor, pyrotinib. PATIENTS AND METHODS:Using patient-derived organoids and xenografts established from an HER2-A775_G776YVMA-inserted advanced lung adenocarcinoma patient sample, we investigated the antitumor activity of pyrotinib. Preliminary safety and efficacy of pyrotinib in 15 HER2-mutant NSCLC patients in a phase II clinical trial are also presented. RESULTS:Pyrotinib showed significant growth inhibition of organoids relative to afatinib in vitro (P?=?0.0038). In the PDX model, pyrotinib showed a superior antitumor effect than afatinib (P?=?0.0471) and T-DM1 (P?=?0.0138). Mice treated with pyrotinib displayed significant tumor burden reduction (mean tumor volume, -52.2%). In contrast, afatinib (25.4%) and T-DM1 (10.9%) showed no obvious reduction. Moreover, pyrotinib showed a robust ability to inhibit pHER2, pERK and pAkt. In the phase II cohort of 15 patients with HER2-mutant NSCLC, pyrotinib 400?mg resulted in a objective response rate of 53.3% and a median progression-free survival of 6.4?months. CONCLUSION:Pyrotinib showed activity against NSCLC with HER2 exon 20 mutations in both patient-derived organoids and a PDX model. In the clinical trial, pyrotinib showed promising efficacy. CLINICAL TRIAL REGISTRATION:NCT02535507.
Project description:PURPOSE:Pyrotinib is a newly-developed irreversible pan-ErbB receptor tyrosine kinase inhibitor. This study reported the first real-world data of pyrotinib-based therapy in metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), focusing on efficacy in lapatinib-treated patients and in brain metastasis. Materials and Methods:One hundred thirteen patients with metastatic HER2-positive BC treated with pyrotinib-based therapy in Fudan University Shanghai Cancer Center under non-clinical trial settings from September 1, 2018 to March 1, 2019 were included. RESULTS:Over half patients have received more than two lines of systematic therapy and exposed to two or more kinds of anti-HER2 agents. Most patients received a combined therapy, commonly of pyrotinib plus capecitabine, or vinorelbine or trastuzumab. Median progression-free survival (PFS) was 6.3 months (range, 5.54 to 7.06 months) and objective response rate (ORR) was 29.5%, with two patients (1.9%) achieving complete response. Lapatinib-naïve patients had significantly longer PFS than lapatinib-treated patients (9.0 months vs. 5.4 months, p=0.001). ORR for lapatinib-treated patients was 23.2%. Thirty-one of 113 patients have brain metastasis. Median PFS was 6.7 months and intracranial ORR was 28%. For patients without concurrent radiotherapy and/or brain surgery, the ORR was very low (6.3%). But for patients receiving concurrent radiotherapy and/or brain surgery, the ORR was 66.7%, and three patients achieved complete response. Most common adverse event was diarrhea. CONCLUSION:Pyrotinib-based therapy demonstrated promising effects in metastatic HER2-positive BC and showed activity in lapatinib-treated patients. For patients with brain metastasis, pyrotinib-based regimen without radiotherapy showed limited efficacy, but when combined with radiotherapy it showed promising intracranial control.
Project description:Abstract The clinical benefits of HER2 inhibitors in patients with non-small cell lung cancer (NSCLC) have been limited. There is a paucity of effective therapies in NSCLC after developing resistance to initial anti-HER2 therapy. Herein, we presented the clinical benefit of pyrotinib in a 53-year-old patient with advanced lung adenocarcinoma whose circulating tumor DNA (ctDNA) analysis of pleural effusion revealed the coexistence of HER2 exon 20 p.Y772_A775dup (mutation ratio: 38.86%) and HER2 amplification (copy number: 4.5) following failures of multiple therapies including afatinib and ado-trastuzumab emtansine (T-DM1). Notably, pyrotinib treatment induced rapid and marked improvement of clinical symptoms, and partial response was observed after 8 weeks. CtDNA monitoring during the treatment showed that the mutation ratio of HER2 decreased to 7.99%, and the amplification disappeared. The patient achieved a progression-free survival of 7.5 months after treatment with pyrotinib. Thus, pyrotinib may be a new treatment strategy for the subgroup of lung adenocarcinoma patients, with coexistence of HER2 exon 20 p.Y772_A775dup and HER2 amplification even after failures of multiple anti-HER2 therapies. It also indicated the value of capture-based next-generation sequencing to monitor and guide therapy.
Project description:Human epidermal growth factor receptor 2 (HER2) has been verified as a valuable biomarker and treatment target in metastatic colorectal cancer (mCRC). Pyrotinib, a novel irreversible HER2/epidermal growth factor receptor (EGFR) dual tyrosine kinase inhibitor, can efficiently inhibit the proliferation of HER2-positive cancer cells in many tumors. We report a case of a 40-year-old woman with both HER2- and EGFR-amplified metastatic colon cancer, who developed refractory disease resistant to multiline therapies (including trastuzumab with lapatinib) but achieved a remarkable response after pyrotinib treatment. For patients with HER2-positive mCRC, who have developed resistance to trastuzumab and lapatinib, pyrotinib is a promising new candidate, which can be used as salvage therapy.
Project description:Background:Overexpression of human epidermal growth factor receptor 2 (HER2) is associated with aggressive disease and poor prognosis. Traditional HER2-targeted agents can improve clinical outcome and have played an essential role in therapy. Pyrotinib is a newly irreversible tyrosine kinase inhibitor (TKI) that is well developed for the treatment of HER2-positive advanced breast tumors. Case Presentation:A 37-year-old postpartum female was presented at a local hospital and was diagnosed with HER2-positive stage IIIB (cT4N1M0) invasive micropapillary adenocarcinoma in the left breast with left axillary metastatic lymph nodes. The patient failed to respond to two cycles of the doxorubicin plus cyclophosphamide (AC) regimen but achieved clinical partial response (cPR) after 4 cycles of the combination of pyrotinib, trastuzumab, paclitaxel and cisplatin (PTPC) regimen according to radiologic assessments. Then, she underwent left-side modified radical mastectomy (MRM) and achieved pathologic complete response (pCR), as confirmed by postoperative pathology. The patient held on receiving 2 cycles of the targeted therapy plus chemotherapy with trastuzumab, paclitaxel plus cisplatin (TPC) and adjuvant radiation therapy but continued to receive targeted therapy with trastuzumab and pertuzumab during the 1-year follow-up period. There has been no clinical evidence of disease progression so far. Conclusion:Breast cancer overexpressing HER2 is a malignant tumor responsible for many cancer-related deaths. The combination of pyrotinib plus other targeted chemotherapy can dramatically improve the outcome of locally advanced disease.
Project description:<h4>Background</h4>Epidermal growth factor receptor (EGFR) is suggested to predict the radiosensitivity and/or prognosis of human esophageal squamous cell carcinoma (ESCC). The objective of this study was to investigate the efficacy of Nimotuzumab (an anti-EGFR monoclonal antibody) on ESCC radiotherapy (RT) and underlying mechanisms.<h4>Methods</h4>Nimotuzumab was administrated to 2 ESCC cell lines KYSE30 and TE-1 treated with RT. Cell growth, colony formation and apoptosis were used to measure anti-proliferation effects. The method of RNA interference was used to investigate the role of insulin-like growth factor binding protein-3 (IGFBP-3) in ESCC cells radiosensitivity treated with Nimotuzumab. In vivo effect of Nimotuzumab on ESCC radiotherapy was done using a mouse xenograft model.<h4>Results</h4>Nimotuzumab enhanced radiation response of KYSE30 cells (with high EGFR expression) in vitro, as evidenced by increased radiation-inhibited cell growth and colony formation and radiation-mediated apoptosis. Mechanism study revealed that Nimotuzumab inhibited phosphorylated EGFR (p-EGFR) induced by EGF in KYSE30 cells. In addition, knockdown of IGFBP-3 by short hairpin RNA significantly reduced KYSE30 cells radiosensitivity (P<0.05), and even after the administration of Nimotuzumab, the RT response of IGFBP-3 silenced KYSE30 cells was not enhanced (P>0.05). In KYSE30 cell xenografts, Nimotuzumab combined with radiation led to significant tumor growth delay, compared with that of radiation alone (P=0.029), and also with IGFBP-3 up-regulation in tumor tissue.<h4>Conclusions</h4>Nimotuzumab could enhance the RT effect of ESCC cells with a functional active EGFR pathway. In particular, the increased ESCC radiosensitivity by Nimotuzumab might be dependent on the up-regulation of IGFBP-3 through EGFR-dependent pathway.
Project description:Background:Previous studies have suggested the efficacy of HER2 antibody (trastuzumab) in scrotal Paget's disease with HER2 amplification or overexpression. However, no report about the effectiveness of HER2 inhibitor (pyrotinib) in those patients has been provided until now. Case Presentation:We present a case of a Chinese patient with bone-metastatic scrotal Paget's disease harboring triple uncommon HER2 mutations (R678Q/S310Y/S310F). Due to poor conditions (severe anemia, thrombocytopenia, ECOG PS3), this patient could not tolerate traditional chemotherapy and radiotherapy. Then, the patient participated in a registered clinical trial (NCT03239015) about basket trial for intractable cancer. The patient received pyrotinib (400 mg po qd) and achieved a partial response for 4.0 months. Conclusion:This is the first report describing a patient with scrotal Paget's disease harboring triple uncommon HER2 mutation who responds well to pyrotinib. This case suggested that HER2 mutation is also a potential biomarker for treatment in extramammary Paget's disease and pyrotinib may be an ideal choice for these patients.
Project description:Background: Pyrotinib, an irreversible pan-ERBB inhibitor, has shown promising antitumour activity, and acceptable tolerability. This research was conducted to evaluate the actual use and effectiveness of pyrotinib in China, therefore, contributed to solve the problem of real-world data scarcity. Methods: In this retrospective study, 168 patients who received pyrotinib treatment for HER2-positive metastatic breast cancer (MBC) in Hunan Province from June 2018 to August 2019 were included. Progression-free survival (PFS), tumor mutation burden (TMB), and drug-related adverse events (AEs) after pyrotinib administration were analyzed. Results: The median PFS (mPFS) time in the 168 participants was 8.07 months. The mPFS times in patients with pyrotinib in second-line therapy (n = 65) and third-or-higher-line therapy (n = 94) were 8.10 months and 7.60 months, respectively. Patients with brain metastases achieved 8.80 months mPFS time. In patients with pyrotinib in third-or-higher-line therapy, patients who had previously used lapatinib still got efficacy but showed a shorter mPFS time (6.43 months) than patients who had not (8.37 months). TMB was measured in 28 patients, K-M curve (P = 0.0024) and Multivariate Cox analysis (P = 0.0176) showed a significant negative association between TMB and PFS. Diarrhea occurred in 98.2% of participants (in any grade) and 19.6% in grade 3-4 AEs. Conclusion: Pyrotinib is highly beneficial to second-or-higher-line patients or HER2-positive MBC patients with brain metastases. Pyrotinib seems to be a feasible strategy both in combination of chemotherapeutic drugs or as a replacement of lapatinib if diseases progressed. TMB could be a potential predictor for evaluating pyrotinib's effectiveness in HER2-positive MBC.