Strategies to overcome acquired resistance to EGFR TKI in the treatment of non-small cell lung cancer

Gao, Jing; Li, Hao-Ran; Jin, Cheng; Jiang, Jingwei; Ding, Jianyong

doi:10.1007/s12094-019-02075-1

Cited by 84 publications

(68 citation statements)

References 129 publications

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“…The alteration of oncogenes, including activating mutation of EGFR, rearrangements of ALK and ROS1, and V600E mutation of BRAF, are considered as a driving force for NSCLC tumorigenesis Targeted therapy for these driver mutations improves the progression-free survival (PFS) significantly compared to the traditional chemo/ radiotherapy. 1,[27][28][29] In the present study, we demonstrated that Tan IIA inhibits NSCLC through suppression of EGFR signaling. Tan IIA reduces the phosphorylation of both wild type (A549) and activating mutant (HCC827 and H1975) EGFR in NSCLC cells.…”

Section: Discussionsupporting

confidence: 57%

<p>Inhibition of EGFR Signaling and Activation of Mitochondrial Apoptosis Contribute to Tanshinone IIA-Mediated Tumor Suppression in Non-Small Cell Lung Cancer Cells</p>

Gao

Liu

et al. 2020

OTT

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Background: Deregulation of epidermal growth factor receptor (EGFR) signaling plays a critical role in non-small cell lung cancer (NSCLC) tumorigenesis. The natural product Tanshinone IIA (Tan IIA) exhibits significant anti-tumor effect in various human cancers, however, the mechanism remains elusive. Methods: The inhibitory effect of Tan IIA NSCLC cells was determined by MTS and soft agar assays. The activation of EGFR signaling and the protein level of myeloid cell leukemia 1 (Mcl-1) were examined by immunoblot (IB), immunohistochemical staining (IHC), and ubiquitination analysis. The in vivo anti-tumor effect was validated by the xenograft mouse model. Results: Tan IIA inhibits NSCLC cells through suppression of EGFR signaling. Tan IIA decreases cell viability and colony formation in EGFR wild type and activating mutant cell lines. The IB data further confirmed that Tan IIA suppresses EGFR phosphorylation timeand dose-dependently. Tan IIA destabilizes Mcl-1 and shortens the half-life. Ubiquitination analysis showed that treatment with Tan IIA promotes Mcl-1 ubiquitination and degradation. Further study showed that the downregulation of EGFR-Akt signaling is required for Tan IIA-induced Mcl-1 reduction. Ectopic overexpression of constitutively activated Akt1 compromised these antitumor efficacies in Tan IIA-treated NSCLC cells. Finally, Tan IIA inhibited the in vivo tumor growth. Conclusion: Our data indicate that Tan IIA acts as an EGFR signaling inhibitor, and targeting EGFR-Akt-Mcl1 axis could provide a new option for NSCLC treatment.

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Section: Discussionsupporting

confidence: 57%

<p>Inhibition of EGFR Signaling and Activation of Mitochondrial Apoptosis Contribute to Tanshinone IIA-Mediated Tumor Suppression in Non-Small Cell Lung Cancer Cells</p>

Gao

Liu

et al. 2020

OTT

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“…Several mechanisms of acquired resistance have been identified, and over one-half of the cases of first-generation TKI resistance were related to the T790M secondary mutation in exon 20 of EGFR. Also, c-MET amplification, overexpression or hyperactivation of other tyrosine kinase receptors, such as ErbB2 and insulin-like growth factor 1 receptor (IGF1R), and PIK3CA and/or K-ras mutations have also been identified to associate with acquired resistance [6][7][8][9] . Although TKI resistance has increased clinically, the treatment strategies to successfully overcome NSCLC TKI resistance are still limited.…”

Section: Introductionmentioning

confidence: 99%

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

Gao

et al. 2020

Cell Death Dis

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Activating mutations of epidermal growth factor receptor (EGFR) play crucial roles in the oncogenesis of human nonsmall cell lung cancer (NSCLC). By screening 79 commercially available natural products, we found that the natural compound deguelin exhibited a profound anti-tumor effect on NSCLC via directly down-regulating of EGFR-signaling pathway. Deguelin potently inhibited in vitro EGFR kinase activity of wild type (WT), exon 19 deletion, and L858R/ T790M-mutated EGFR. The in silico docking study indicated that deguelin was docked into the ATP-binding pocket of EGFRs. By suppression of EGFR signaling, deguelin inhibited anchorage-dependent, and independent growth of NSCLC cell lines, and significantly delayed tumorigenesis in vivo. Further study showed that deguelin inhibited EGFR and downstream kinase Akt, which resulted in the activation of GSK3β and eventually enhanced Mcl-1 phosphorylation at S159. Moreover, deguelin promoted the interaction between Mcl-1 and E3 ligase SCF FBW7 , which enhanced FBW7-mediated Mcl-1 ubiquitination and degradation. Additionally, phosphorylation of Mcl-1 by GSK3β is a prerequisite for FBW7-mediated Mcl-1 destruction. Depletion or pharmacological inactivation of GSK3β compromised deguelin-induced Mcl-1 ubiquitination and reduction. Taken together, our data indicate that enhancement of ubiquitination-dependent Mcl-1 turnover might be a promising approach for cancer treatment.

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“…Approximately 51% of patients present with advanced disease at diagnosis . The standard of care in patients with advanced disease is platinum‐based doublet chemotherapy . Although chemotherapy has improved the outcome and quality of life of patients, the prognosis remains unfavorable, with a median survival time that does not exceed 10 months .…”

Section: Introductionmentioning

confidence: 99%

Experimental study of the vascular normalization window for tumors treated with apatinib and the efficacy of sequential chemotherapy with apatinib in lung cancer‐bearing mice and patients

Liu

Wang

et al. 2020

Cancer Medicine

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In the tumor vascular system, the vascular structure is disordered, the morphology is abnormal, and the structure of the blood vessel walls is incomplete, leading to leakage of the blood vessel wall, elevated interstitial fluid pressure, and elevated blood flow resistance. These alterations lead to local microenvironmental changes, which mainly manifest as a lack of oxygen and acidosis, further affecting the efficacy of chemotherapy drugs. Antiangiogenic drugs can normalize the abnormalities caused by tumor angiogenesis, thereby transferring oxygen and drugs to tumor cells more efficiently through normalized blood vessels and enhancing the efficacy of chemotherapy drugs. Apatinib is a specific VEGFR-2 inhibitor that blocks the transmission of the VEGF/VEGFR-2 signaling pathway. In this study, we constructed a nude mouse xenograft model of lung cancer and administered apatinib at different doses and times to detect the normalization of reactive blood vessels through VEGF, α-SMA, college-IV, HIF-1α, and MMP. The ultrastructure of tumor blood vessels was observed by electron microscopy, and the dose and timing of apatinib-induced normalization of lung cancer in nude mice were confirmed. Then, we observed the inhibitory effect of apatinib combined with pemetrexed on transplanted tumors of lung cancer cells in nude mice at different time points and observed whether combination pemetrexed chemotherapy showed more significant effects in the time window of vascular normalization induced by apatinib. The inhibition of the growth of transplanted tumors was examined. Then 20 patients with advanced non-small cell lung cancer were enrolled, and apatinib sequential chemotherapy drugs were applied as a third-line chemotherapy regimen to observe its clinical efficacy.

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Strategies to overcome acquired resistance to EGFR TKI in the treatment of non-small cell lung cancer

Cited by 84 publications

References 129 publications

<p>Inhibition of EGFR Signaling and Activation of Mitochondrial Apoptosis Contribute to Tanshinone IIA-Mediated Tumor Suppression in Non-Small Cell Lung Cancer Cells</p>

<p>Inhibition of EGFR Signaling and Activation of Mitochondrial Apoptosis Contribute to Tanshinone IIA-Mediated Tumor Suppression in Non-Small Cell Lung Cancer Cells</p>

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

Experimental study of the vascular normalization window for tumors treated with apatinib and the efficacy of sequential chemotherapy with apatinib in lung cancer‐bearing mice and patients

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