Anlotinib can overcome acquired resistance to <scp>EGFR‐TKIs</scp> via <scp>FGFR1</scp> signaling in non‐small cell lung cancer without harboring <scp>EGFR T790M</scp> mutation

Lian, Zengzhi; Du, Wenwen; Zhang, Yang; Fu, Yulong; Liu, Ting; Wang, Anqi; Cai, Tingting; Zhu, Jianjie; Zeng, Yuanyuan; Liu, Zeyi; Huang, Jian-An

doi:10.1111/1759-7714.13485

Cited by 24 publications

(19 citation statements)

References 36 publications

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“…These data suggest that anlotinib-induced apoptosis may be the result of elevated intracellular ROS, which may function as upstream regulators of the p38/JNK MAPK and ERK pathways. In contrast, other studies have shown that anlotinib attenuates ERK activation in diverse cancer cells (Yang Q. et al, 2020;Hu et al, 2020;Lian et al, 2020). Cagnol et al reported that ERK activity depends on the presence of ROS (Cagnol and Chambard, 2010).…”

Section: Discussionmentioning

confidence: 93%

Metformin Potentiates the Effects of Anlotinib in NSCLC via AMPK/mTOR and ROS-Mediated Signaling Pathways

et al. 2021

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Anlotinib is a novel multi-targeted tyrosine kinase inhibitor with activity against soft tissue sarcoma, small cell lung cancer, and non-small cell lung cancer (NSCLC). Potentiating the anticancer effect of anlotinib in combination strategies remains a clinical challenge. Metformin is an oral agent that is used as a first-line therapy for type 2 diabetes. Interesting, metformin also exerts broad anticancer effects through the activation of AMP-activated protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR). Here, we evaluated the possible synergistic effect of anlotinib and metformin in NSCLC cells. The results showed that metformin enhanced the antiproliferative effect of anlotinib. Moreover, anlotinib combined with metformin induced apoptosis and oxidative stress, which was associated with the activation of AMPK and inhibition of mTOR. Reactive oxygen species (ROS)- mediated p38/JNK MAPK and ERK signaling may be involved in the anticancer effects of this combination treatment. Our results show that metformin potentiates the efficacy of anlotinib in vivo by increasing the sensitivity of NSCLC cells to the drug. These data provide a potential rationale for the combination of anlotinib and metformin for the treatment of patients with NSCLC or other cancers.

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Section: Discussionmentioning

confidence: 93%

Metformin Potentiates the Effects of Anlotinib in NSCLC via AMPK/mTOR and ROS-Mediated Signaling Pathways

et al. 2021

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“…PC9GR and HCC827GR cells were highly insensitive to gefitinib compared to their respective parental cells (Additional file 2 : Fig S1). Our previous work showed that the PC9GR cell line harbours EGFR 19del and T790M mutations; the HCC827GR cell line harbours the EGFR 19del mutation and overexpresses FGFR1 and AXL [ 26 , 27 ]. To investigate whether there are other mechanisms responsible for acquired resistance to EGFR-TKIs in addition to variations such as the T790M mutation, MET amplification and overexpression of FGFR1 and AXL, we examined expression of soluble receptors and related proteins in PC9GR and HCC827GR cells by proteome profiler array analysis.…”

Section: Resultsmentioning

confidence: 99%

“…5 b). Given that osimertinib is an oral, irreversible EGFR-TKI that is selective for both EGFR and T790M resistance mutations [ 32 ], we also evaluated p-FAK in T790M mutant cells (PC9GR and H1975) treated with osimertinib [ 25 , 27 ]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Abnormally activated OPN/integrin αVβ3/FAK signalling is responsible for EGFR-TKI resistance in EGFR mutant non-small-cell lung cancer

Zhang

et al. 2020

J Hematol Oncol

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Background Acquired epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance limits the long-term clinical efficacy of tyrosine kinase-targeting drugs. Although most of the mechanisms of acquired EGFR-TKI resistance have been revealed, the mechanism of ~ 15% of cases has not yet been elucidated. Methods Cell viability was analysed using the Cell Counting Kit-8 (CCK-8) assay. Proteome profiler array analysis was performed to find proteins contributing to acquired EGFR-TKI resistance. Secreted OPN was detected by ELISA. Immunohistochemical analysis was conducted to detect expression of integrin αV in NSCLC tissue. The effect of VS-6063 on apoptosis and proliferation of PC9 gefitinib-resistant cells was detected by fluorescence-activated cell sorting (FACS) and clonogenic assays. A mouse xenograft model was used to assess the effect of VS-6063 on the sensitivity of PC9 gefitinib-resistant cells to gefitinib. Results OPN was overexpressed in acquired EGFR-TKI-resistant NSCLCs. Secreted OPN contributed to acquired EGFR-TKI resistance by activating the integrin αVβ3/FAK pathway. Inhibition of FAK signalling increased sensitivity to EGFR-TKIs in PC9 gefitinib-resistant cells both in vitro and in vivo. Conclusions OPN contributes to acquired EGFR-TKI resistance by up-regulating expression of integrin αVβ3, which activates the downstream FAK/AKT and ERK signalling pathways to promote cell proliferation in NSCLC.

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“…The main acquired resistance mechanisms appear to be secondary mutations of EGFR (T790M), KRAS , PIK3CA and MET amplification. A recent study suggested that anlotinib could overcome acquired resistance to EGFR-TKI via inhibiting FGFR1 ( 31 ). A preclinical study showed that anlotinib could inhibit proliferation and induce apoptosis of KRAS mutation lung cancer cells through downregulating MEK and ERK.…”

Section: Discussionmentioning

confidence: 99%

Real-World Efficacy and Safety of Anlotinib With and Without Immunotherapy in Advanced Non-Small Cell Lung Cancer

Xiong

Qin

Xin³

et al. 2021

Front. Oncol.

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AimsCombination of anti-angiogenesis therapy and immunotherapy has showed synergistic effects in non-small cell lung cancer (NSCLC). The aim of this retrospective study was to investigate the efficacy and safety of anlotinib with and without immunotherapy in NSCLC.MethodsPathologically confirmed NSCLC patients (stage IIIB-IV) receiving anlotinib between November 2018 and February 2020 were enrolled for retrospective analysis. The outcomes and safety of overall patients were evaluated, and the efficacies of anlotinib plus immunotherapy and anlotinib alone was compared. The primary endpoint was progression-free survival (PFS).ResultsA total of 80 patients (median age: 62 years, range: 29-86 years) were included. Overall median PFS was 4.3 months (95% confidence interval (CI): 2.7-5.9 months). In univariate analysis, patients without EGFR mutation, previous EGFR target therapy, and brain metastasis had significantly longer PFS. Cox regression analysis showed that only brain metastasis was an independent predictor of PFS. The median PFS of patients receiving anlotinib plus immunotherapy was slightly longer than that of patients receiving anlotinib alone (4.2 vs 3.1 months); however, the difference was not statistically significant. A tendency of longer median PFS was observed in patients with adenocarcinoma, EGFR wild type, stage IV, no liver metastasis, former smoker, ≥2 previous treatment lines, no previous VEGF or EGFR target therapies in anlotinib plus immunotherapy group. Treatments with anlotinib alone or anlotinib plus immunotherapy were well tolerable. The most common adverse events were fatigue, decreased hemoglobin count, hypertension, hand-foot syndrome, oral mucositis and hoarseness.ConclusionAnlotinib is well tolerable and effective in advanced NSCLC patients. Brain metastasis is an independent predictor of PFS in NSCLC patients receiving anlotinib. Future prospective studies with larger sample size and extended follow-up are needed to confirm the clinical benefit in NSCLC patients treated with anlotinib combined with immunotherapy.

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Anlotinib can overcome acquired resistance to EGFR‐TKIs via FGFR1 signaling in non‐small cell lung cancer without harboring EGFR T790M mutation

Cited by 24 publications

References 36 publications

Metformin Potentiates the Effects of Anlotinib in NSCLC via AMPK/mTOR and ROS-Mediated Signaling Pathways

Metformin Potentiates the Effects of Anlotinib in NSCLC via AMPK/mTOR and ROS-Mediated Signaling Pathways

Abnormally activated OPN/integrin αVβ3/FAK signalling is responsible for EGFR-TKI resistance in EGFR mutant non-small-cell lung cancer

Real-World Efficacy and Safety of Anlotinib With and Without Immunotherapy in Advanced Non-Small Cell Lung Cancer

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