Synergistic effects of crizotinib and radiotherapy in experimental EML4–ALK fusion positive lung cancer

Dai, Ying; Wei, Quan-Xiang; Schwager, Christian; Moustafa, Mahmoud; Zhou, Cheng; Lipson, Kenneth E.; Weichert, Wilko; Debus, Jürgen; Abdollahi, Amir

doi:10.1016/j.radonc.2014.12.009

Cited by 50 publications

(45 citation statements)

References 31 publications

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“…This is in line with recently reported data on differential phosphoproteome response of NSCLC cells to conventional radiotherapy vs. proton and carbon irradiation [ 29 ]. Together with data of enhanced eradication of otherwise radioresistant tumor stem cells by carbon ions, these data indicate further exploration of distinct radiobiological features of different radiation qualities [ 30 ]. The potent sensitizing effects of TAE684 on carbon ions observed in ALK-positive H3122 cells (SER: 1.61) suggest further evaluation of this combination in the emerging field of high-LET particle therapy.…”

Section: Discussionmentioning

confidence: 94%

Oncogene addiction and radiation oncology: effect of radiotherapy with photons and carbon ions in ALK-EML4 translocated NSCLC

et al. 2018

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BackgroundPatients with Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) positive lung cancer are sensitive to ALK-kinase inhibitors. TAE684 is a potent second generation ALK inhibitor that overcomes Crizotinib resistance. Radiotherapy is an integral therapeutic component of locally advanced lung cancer. Therefore, we sought to investigate the effects of combined radiotherapy and ALK-inhibition via TAE684 in ALK-positive vs. wild type lung cancer cells.MethodsHuman non-small cell lung cancer (NSCLC) cell lines harboring wild-type ALK (A549), EML4-ALK translocation (H3122) and murine Lewis Lung Cancer (LLC) cells were investigated. Cells were irradiated with 1–4 Gy X-Rays (320 keV) and carbon ions (Spread-out Bragg Peak, SOBP (245.4–257.0 MeV/u)) at Heidelberg Ion Therapy center. TAE684 was administered at the dose range 0–100 nM. Clonogenic survival, proliferation and apoptosis via caspase 3/7 expression level were assessed in all three cell lines using time-lapse live microscopy.ResultsTAE684 inhibited the proliferation of H3122 cells in a dose-dependent manner with a half maximal inhibitory concentration (IC50) of ~ 8.2 nM. However, A549 and LLC cells were relatively resistant to TAE684 and IC50 was not reached at concentrations tested (up to 100 nM) in proliferation assay. The antiproliferative effect of TAE684 was augmented by radiotherapy in H3122 cells. TAE684 significantly sensitized H3122 cells to particle therapy with carbon ions (sensitizer enhancement ratio ~1.61, p < 0.05). Caspase 3/7 activity was evidently enhanced after combination therapy in H3122 cells.ConclusionsThis is the first report demonstrating synergistic effects of combined TAE684 and radiotherapy in EML4-ALK positive lung cancer cells. In addition to conventional photon radiotherapy, ALK-inhibition also enhanced the effects of particle irradiation using carbon ions. Our data indicate beneficial effects of combined ALK-inhibition and radiotherapy in treatment of this distinct subpopulation of NSCLC that warrant further evaluation.

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Section: Discussionmentioning

confidence: 94%

Oncogene addiction and radiation oncology: effect of radiotherapy with photons and carbon ions in ALK-EML4 translocated NSCLC

et al. 2018

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“…A previous study reported that beneficial effects of crizotinib on ALK-positive NSCLC are elicited in combination with radiotherapy [28]. miRNAs play a critical role in the development of NSCLC and are considered as potential biomarkers for NSCLC diagnosis and therapy [29, 30].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of MicroRNA-21-5p Promotes the Radiation Sensitivity of Non-Small Cell Lung Cancer Through HMSH2

Zuo

Qian

et al. 2017

Cell Physiol Biochem

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Background: This study aimed to explore the effects of microRNA-21-5p (miR-21-5p) on the radiation sensitivity of non-small cell lung cancer (NSCLC) and the involvement of human MutS homolog 2 (hMSH2) One hundred fourteen NSCLC patients at stage II or III who received surgery and postoperative radiotherapy were enrolled in this study. Methods: The patients were assigned into radiation-sensitive and -insensitive groups. NSCLC A549 cells were transfected to generate control, Negative control (NC), miR-21-5p inhibitor, miR-21-5p mimic, small interfering hMSH2 (sihMSH2), miR-21-5p inhibitor + sihMSH2 and hMSH2 overexpression groups. Immunohistochemistry was performed to detect the hMSH2 expression in transfected and irradiated cells. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were performed to evaluate A549 miR-21-5p and hMSH2 expression in transfected and irradiated cells. A colony formation assay was adopted for cell survival analysis. The relationship between miR-21-5p and hMSH2 was verified by a luciferase reporter assay. Cell viability was measured by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and apoptosis was assessed by flow cytometry. NSCLC nude mouse models were established, and tumor volumes and tumor weights were recorded. Results: The radiation-sensitive group of patients exhibited lower miR-21-5p but higher hMSH2 expression than the insensitive group. For irradiated A549 cells, lower cell survival, higher apoptosis, increased miR-21-5p expression and decreased hMSH2 expression were observed at 6 and 8 Gy than at 0, 2 and 4 Gy; compared to 6 Gy, cell survival and hMSH2 expression were decreased and apoptosis and miR-21-5p expression were increased at 8 Gy. Additionally, miR-21-5p was found to target hMSH2. Compared with the control group, the cell survival rate was lower and the apoptosis rate higher in the miR-21-5p inhibitor group, whereas the opposite was observed for the miR-21-5p mimic and sihMSH2 groups. For the mouse model, decreased tumor volume and tumor weight and higher hMSH2 expression were found in the miR-21-5p inhibitor, radiation, hMSH2 overexpression, miR-21-5p inhibitor + radiation and hMSH2 overexpression + radiation groups compared with the control group. In addition, tumor volume and tumor weight were decreased and hMSH2 expression increased in the miR-21-5p inhibitor + radiation and hMSH2 overexpression + radiation groups compared with the radiation alone group. Conclusion: These findings indicate that inhibition of miR-21 can promote the radiation sensitivity of NSCLC by targeting hMSH2.

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“…Recently, synergistic effects between radiation and tyrosine kinase inhibitors (TKIs) targeting ALK rearrangement have been demonstrated [21][22] and, under certain circumstances, radiotherapy may improve survival in patients with advanced oncogene-driven NSCLC [23][24]. During this study, we screened 187 ALK-positive metastatic NSCLC patients and identified 27 patients with SBM, the synchronous brain metastasis frequency of patients with in ALK-rearranged non-small cell lung cancer is 14.4%.…”

Section: Resultsmentioning

confidence: 99%

Radiographic Features of Metastatic Brain Tumors from ALK-rearranged Non-small Cell Lung Cancer: Implications for Optimal Treatment Modalities

Chu

Yang

et al. 2019

J. Cancer

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Purpose: To investigate the radiological features on magnetic resonance imaging (MRI) of brain metastases (BM) from ALK-rearranged non-small cell lung cancer (NSCLC). Patients and Methods: We retrospectively evaluated data from 40 eligible patients with ALK-rearranged NSCLC. Radiographic features of metastatic brain tumors, including the number, size, location, and peritumoral brain edema size (PBES), were delineated using MRI. Results: 13 patients had metachronous BM (MBM), having developed BM at least 6 months after diagnosis with NSCLC. The remaining patients were categorized as having synchronous BM (SBM). Compared with patients in the SBM group, patients in the MBM group were found to have more favorable values for radiological features including BM number, BM size, and PBES. Ten (76.9%) of the 13 patients with MBM had ≤3 lesions and were asymptomatic, and none had developed a diffuse BM pattern, supporting the adoption of stereotactic radiosurgery (SRS) in the majority of these patients and against the administration of prophylactic cranial irradiation (PCI). Conversely, among the 27 patients with SBM, 15 (55.6%) patients had >3 lesions and 12 (44.4%) patients were symptomatic, highlighting the necessity of rapidly administrating brain radiotherapy, either as SRS or whole brain radiotherapy (WBRT). Importantly, only two patients (5.0%) had metastases in the hippocampus and peri-hippocampus region, and both were in the SBM group, indicating the feasibility of hippocampal avoidance WBRT in ALK-rearranged NSCLC. Conclusions: Both WBRT and SRS are appropriate for the treatment of BM in patients with ALK-rearranged NSCLC. The incidence of BM in the hippocampus and peri-hippocampus region is low in our radiological data. Nearly 80% of patients with metachronous BM have oligo-metastatic lesions, indicating that SRS is the preferred therapy while PCI is not indicated.

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Synergistic effects of crizotinib and radiotherapy in experimental EML4–ALK fusion positive lung cancer

Cited by 50 publications

References 31 publications

Oncogene addiction and radiation oncology: effect of radiotherapy with photons and carbon ions in ALK-EML4 translocated NSCLC

Oncogene addiction and radiation oncology: effect of radiotherapy with photons and carbon ions in ALK-EML4 translocated NSCLC

Inhibition of MicroRNA-21-5p Promotes the Radiation Sensitivity of Non-Small Cell Lung Cancer Through HMSH2

Radiographic Features of Metastatic Brain Tumors from ALK-rearranged Non-small Cell Lung Cancer: Implications for Optimal Treatment Modalities

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