VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene‐driven non‐small‐cell lung cancers

Watanabe, Hiromi; Ichihara, Eiki; Kayatani, Hiroe; Makimoto, Go; Ninomiya, Kiichiro; Nishii, Kazuya; Higo, Hisao; Ando, Chihiro; Okawa, Sachi; Nakasuka, Takamasa; Kano, Hirohisa; Hara, Naofumi; Hirabae, Atsuko; Kato, Yuka; Ninomiya, Takashi; Kubo, Toshio; Rai, Kammei; Ohashi, Kadoaki; Hotta, Katsuyuki; Tabata, Masahiro; Maeda, Yoshinobu; Kiura, Katsuyuki

doi:10.1111/cas.14801

Cited by 34 publications

(28 citation statements)

References 23 publications

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“…Therefore, these results indicated that apatinib inhibited the growth of NSCLC cells through cell cycle arrest and apoptosis. Many studies have reported that A549 cells expressed a relative low level of VEGFR2 among NSCLC cell lines [36][37][38]. Our results presented evidence that NSCLC cells expressing low levels of VEGFR2 still responded to apatinib.…”

Section: Discussionsupporting

confidence: 66%

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

Xie

Zhou

Liang

et al. 2021

J Exp Clin Cancer Res

105

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Background Recently, a variety of clinical trials have shown that apatinib, a small-molecule anti-angiogenic drug, exerts promising inhibitory effects on multiple solid tumors, including non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism of apatinib on NSCLC remains unclear. Methods MTT, EdU, AO/EB staining, TUNEL staining, flow cytometry, colony formation assays were performed to investigate the effects of apatinib on cell proliferation, cell cycle distribution, apoptosis and cancer stem like properties. Wound healing and transwell assays were conducted to explore the role of apatinib on migration and invasion. The regulation of apatinib on VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling were detected. Furthermore, we collected conditioned medium (CM) from A549 and H1299 cells to stimulate phorbol myristate acetate (PMA)-activated THP-1 cells, and examined the effect of apatinib on PD-L1 expression in macrophages. The Jurkat T cells and NSCLC cells co-culture model was used to assess the effect of apatinib on T cells activation. Subcutaneous tumor formation models were established to evaluate the effects of apatinib in vivo. Histochemical, immunohistochemical staining and ELISA assay were used to examine the levels of signaling molecules in tumors. Results We showed that apatinib inhibited cell proliferation and promoted apoptosis in NSCLC cells in vitro. Apatinib induced cell cycle arrest at G1 phase and suppressed the expression of Cyclin D1 and CDK4. Moreover, apatinib upregulated Cleaved Caspase 3, Cleaved Caspase 9 and Bax, and downregulated Bcl-2 in NSCLC cells. The colony formation ability and the number of CD133 positive cells were significantly decreased by apatinib, suggesting that apatinib inhibited the malignant and stem-like features of NSCLC cells. Mechanistically, apatinib inhibited PD-L1 and c-Myc expression by targeting VEGFR2/STAT3 signaling. Apatinib also inhibited PD-L1 expression in THP-1 derived macrophages stimulated by CM from NSCLC cells. Furthermore, apatinib pretreatment increased CD69 expression and IFN-γ secretion in stimulated Jurkat T cells co-cultured with NSCLC cells. Apatinib also promoted ROS production and inhibited Nrf2 and p62 expression, leading to the autophagic and apoptotic cell death in NSCLC. Moreover, apatinib significantly inhibited tumor growth in vivo. Conclusion Our data indicated that apatinib induced autophagy and apoptosis in NSCLC via regulating VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling.

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Section: Discussionsupporting

confidence: 66%

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

Xie

Zhou

Liang

et al. 2021

J Exp Clin Cancer Res

105

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“…Preclinical researches and clinical trials have demonstrated that anti-angiogenic drugs combined with EGFR-TKIs is a viable strategy for EGFR -mutant NSCLC patients [ 33 – 36 ]. According to the results of an ongoing phase II clinical trial, impressive objective response rate and disease control rate were obtained with acceptable toxicity after the united medication [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Role of chemokine-mediated angiogenesis in resistance towards crizotinib and its reversal by anlotinib in EML4-ALK positive NSCLC

et al. 2022

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Background The identification of early plasma biomarkers for clinical outcomes and drug resistance has key importance for risk stratification in anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) patients. Moreover, it remains unclear whether the anti-angiogenic drug anlotinib can reverse the resistance of ALK-tyrosine kinase inhibitor (ALK-TKI) crizotinib, and no research has explored the effect of anlotinib combined with crizotinib on ALK-positive patients. Methods In this study, 76 baseline and longitudinal plasma samples from 61 ALK-positive NSCLC patients receiving crizotinib treatment were analyzed by Luminex liquid suspension chip for 40 chemokines. RNA sequence (RNA-seq) was used to identify differentially expressed genes (DEGs) between H3122 and H3122-crizotinib resistant (H3122CR) cells. Tube formation assay was performed to investigate the effect of chemokines on angiogenesis. And H3122CR-derived xenograft model was constructed to validate the efficacy and safety of anlotinib combined with crizotinib in vivo. Results Baseline and progression plasma samples detection suggested that CCL20 played a crucial role in monitoring and predicting the clinical response of crizotinib (hazard ratio for progression-free survival: 2.27 (1.13–4.58); for overall survival: 2.7 (1.23–5.8)). RNA-seq results for H3122 and H3122CR cells showed that high expression of chemokines and angiogenesis pathways were involved in crizotinib resistance. Subsequently, in vitro experiments indicated that CCL20 may induce crizotinib resistance by activation of angiogenesis via JAK2/STAT3-CCL20-VEGFA/IL6 axis. We further found that anti-angiogenic TKI anlotinib could reverse crizotinib resistance by inhibiting chemokines-induced angiogenesis, and anlotinib combined with crizotinib has a better antitumor effect than monotherapy in vitro & in vivo. Conclusions Overall, CCL20-mediated angiogenesis is involved in crizotinib resistance and could be overcome by using anlotinib in EML4-ALK positive NSCLC. The combination of anlotinib and crizotinib is a promising strategy for patients resistant to ALK-TKIs.

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“…Anti-angiogenic agents could also play a role in combination with a TKI. Combining vascular endothelial growth factor (VEGF)-pathway blockade with a TKI targeting ROS-1 in vitro improved the anti-tumor effect compared to TKI alone [ 113 ]. According to a study based on 14 patients, the crizotinib–bevacizumab combination achieved efficacy against ALK-positive, ROS-1-positive or MET-amplified tumors with 58.3% ORR and an acceptable tolerance profile.…”

Section: Treatment Of Ros-1-positive Nsclcsmentioning

confidence: 99%

ROS-1 Fusions in Non-Small-Cell Lung Cancer: Evidence to Date

et al. 2022

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The ROS-1 gene plays a major role in the oncogenesis of numerous tumors. ROS-1 rearrangement is found in 0.9–2.6% of non-small-cell lung cancers (NSCLCs), mostly lung adenocarcinomas, with a significantly higher rate of women, non-smokers, and a tendency to a younger age. It has been demonstrated that ROS-1 is a true oncogenic driver, and tyrosine kinase inhibitors (TKIs) targeting ROS-1 can block tumor growth and provide clinical benefit for the patient. Since 2016, crizotinib has been the first-line reference therapy, with two-thirds of the patients’ tumors responding and progression-free survival lasting ~20 months. More recently developed are ROS-1-targeting TKIs that are active against resistance mechanisms appearing under crizotinib and have better brain penetration. This review summarizes current knowledge on ROS-1 rearrangement in NSCLCs, including the mechanisms responsible for ROS-1 oncogenicity, epidemiology of ROS-1-positive tumors, methods for detecting rearrangement, phenotypic, histological, and molecular characteristics, and their therapeutic management. Much of this work is devoted to resistance mechanisms and the development of promising new molecules.

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VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene‐driven non‐small‐cell lung cancers

Cited by 34 publications

References 23 publications

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

Role of chemokine-mediated angiogenesis in resistance towards crizotinib and its reversal by anlotinib in EML4-ALK positive NSCLC

ROS-1 Fusions in Non-Small-Cell Lung Cancer: Evidence to Date

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