NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor

Galvani, Elena; Sun, Jing; León, Leticia G.; Sciarrillo, Rocco; Narayan, Ravi S.; Sjin, Robert Tjin Tham; Lee, Kwang-Ho; Ohashi, Kadoaki; Heideman, Daniëlle A.M.; Alfieri, Roberta; Heynen, Guus J.J.E.; Bernards, René; Smit, Egbert F.; Pao, William; Peters, Godefridus J.; Giovannetti, Elisa

doi:10.18632/oncotarget.3956

Cited by 30 publications

(25 citation statements)

References 57 publications

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“…15,17 More recently, NF-kB activation was shown to drive resistance to a mutant-selective EGFR inhibitor in T790M mutant cells. 16 While these prior studies indicate that NF-kB signaling supports resistance of EGFR-mutant tumors to TKIs, our findings indicate that NF-kB signaling plays a broader role in EGFR-driven lung carcinogenesis.…”

Section: Discussioncontrasting

confidence: 50%

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Epithelial NF-κB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment

et al. 2016

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Several studies have demonstrated that NF-kB activation is common in lung cancer; however, the mechanistic links between NF-kB signaling and tumorigenesis remain to be fully elucidated. We investigated the function of NF-kB signaling in epidermal growth factor receptor (EGFR)-mutant lung tumors using a transgenic mouse model with doxycycline (dox)-inducible expression of oncogenic EGFR in the lung epithelium with or without a dominant inhibitor of NF-kB signaling. NF-kB inhibition resulted in a significant reduction in tumor burden in both EGFR tyrosine kinase inhibitor (TKI)-sensitive and resistant tumors. However, NF-kB inhibition did not alter epithelial cell survival in vitro or in vivo, and no changes were detected in activation of EGFR downstream signaling pathways. Instead, we observed an influx of inflammatory cells (macrophages and neutrophils) in the lungs of mice with oncogenic EGFR expression that was blocked in the setting of NF-kB inhibition. To investigate whether inflammatory cells play a role in promoting EGFR-mutant lung tumors, we depleted macrophages and neutrophils during tumorigenesis and found that neutrophil depletion had no effect on tumor formation, but macrophage depletion caused a significant reduction in tumor burden. Together, these data suggest that epithelial NFkB signaling supports carcinogenesis in a non-cell autonomous manner in EGFR-mutant tumors through recruitment of pro-tumorigenic macrophages.

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Section: Discussioncontrasting

confidence: 50%

“…[9][10][11][12] EGFR signaling is known to activate NF-kB in a variety of tumor types, 13,14 and NF-kB signaling has been shown to facilitate resistance to EGFR inhibitor therapies in lung cancer. [15][16][17][18] However, the importance of the NF-kB pathway during oncogenic EGFR-driven lung tumorigenesis has not been examined.…”

Section: Introductionmentioning

confidence: 99%

Epithelial NF-κB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment

et al. 2016

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“…These data supported the concept of inhibition of members of the NF-κB pathway as a promising therapeutic option to reduce the viability of cells that adapted to third-generation EGFR-TKIs. 39 …”

Section: Introductionmentioning

confidence: 99%

New developments in the management of non-small-cell lung cancer, focus on rociletinib: what went wrong?

Steen¹,

Caparello²,

Rolfo³

et al. 2016

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Recently, the development of the third-generation epidermal growth factor receptor-small molecule inhibitor (EGFR-TKI) rociletinib had failed. In this review, the wide-ranging aspects of the evolution of EGFR-TKIs were collected, with a special focus on rociletinib. The influence of different oncogenic mutations on EGFR activity was also discussed. Resistance to the first (erlotinib, gefitinib)- and second (afatinib)-generation EGFR-TKIs provided the rationale behind the development of the third-generation inhibitors (rociletinib, osimertinib). On the basis of these data, a comparison of their efficacy on the different mutated EGFRs and the respective resistance mechanisms is further reported. Moreover, the evolution and results of the clinical trials of rociletinib (TIGER trials) are compared with the trials on osimertinib, another third-generation EGFR-TKI that now has been granted US Food and Drug Administration approval. The reasons behind the arrest in the further development of rociletinib are put in the perspective of future drug development.

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“…Inhibition of NF‐κB enhanced sensitivity of oncogene‐addicted NSCLC cells to EGFR‐TKIs . Recently reported NF‐κB signaling played a crucial role in driving new generation EGFR‐TKI‐acquired resistance . To have a better understanding of PC‐9GRCOR and H1975COR cells in mechanism of resistance, we measured family proteins including p50 and p65, and inhibitor proteins of IKBɑ and IKKɑ/β in phosphorylation, which indicate the activity of NF‐κB.…”

Section: Discussionmentioning

confidence: 99%

Metformin synergistically enhances the antitumor activity of the third‐generation EGFR‐TKI CO‐1686 in lung cancer cells through suppressing NF‐κB signaling

Pan

Lin

et al. 2018

Clinical Respiratory J

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Purpose: Third-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), rociletinib (CO-1686), is great efficacy against EGFRmutated patients bearing the T790M resistance mutation. However, acquired resistance may emerge. There is a need to characterize acquired resistance mechanism(s) and to devise ways to overcome CO-1686 resistance. Experimental Design: MTT assay, ki67 incorporation assay, transwell assay and TUNEL assay were employed to analyze the effects of metformin to reverse CO-1686 resistance in vitro. The NF-κB activity was measured by the antibody of p50, p65, p-IKBɑ, and p-IKKɑ/β. Western blotting was used to analyze the proteins in cells. Results:We have established CO-1686-resistant cell lines of PC-9GRCOR and H1975COR from two parental cell lines of PC-9GR and H1975 by long-term exposure to increasing doses of CO-1686. Compared with the parental cells, PC-9GRCOR cells and H1975COR cells showed 90-folds and 20-folds higher resistance to CO-1686, respectively. Critically, we showed that the nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) signaling molecular proteins subunits of p50, p65 and its inhibitor proteins of IKBɑ, IKKɑ/β in phosphorylation levels in resistant cells were higher than parental cells. Accordingly, inhibition of NF-κB activity used TPCA-1 effective in decreasing viability and inducing apoptosis of resistant cells. Moreover, metformin overcame the acquired resistance to CO-1686 by reducing cell proliferation and invasion. Metformin combined with CO-1686 synergistically inhibited the p-IKBɑ, p-IKKɑ/β, p50, and p65. Conclusions: NF-κB signaling activation induced acquired resistance to CO-1686.Metformin sensitized resistant cells to CO-1686 via inhibiting NF-κB signaling. K E Y W O R D Sacquired resistance, CO-1686, metformin, NF-κB | 2643 PAN et al.

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NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor

Cited by 30 publications

References 57 publications

Epithelial NF-κB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment

Epithelial NF-κB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment

New developments in the management of non-small-cell lung cancer, focus on rociletinib: what went wrong?

Metformin synergistically enhances the antitumor activity of the third‐generation EGFR‐TKI CO‐1686 in lung cancer cells through suppressing NF‐κB signaling

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