Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation

Kim, Sun Mi; Kwon, Oh Joon; Hong, Yun; Kim, Joo Hang; Solca, Flavio; Ha, Sang Jun; Soo, Ross A.; Christensen, James G.; Lee, Ji Hyun; Cho, Byoung Chul

doi:10.1158/1535-7163.mct-12-0311

Cited by 178 publications

(168 citation statements)

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“…[26][27][28] An increased autocrine stimulation of the IL-6/STAT3 pathway could unleash the cells from their dependency on EGFR. 27) Notably, increased levels of IL-6 was reported in around 30% of NSCLC patients and in EGFR-TKI treated cell culture.…”

Section: Discussionmentioning

confidence: 99%

“…Since EMT has been previously reported to be associated with erlotinib resistance and IL-6 activation was reported as a key mechanism underlying EGFR-TKI resis- tance, 11,[26][27][28][29] We examined the IL-6 secretion of HCC827-ER cells. Culture supernatant from HCC827-ER cells contained significantly higher levels of IL-6 as compared with parental cells.…”

Section: Acquired Resistance Of the Egfr-tki Inhibitor Erlotinib In Hmentioning

confidence: 99%

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Polyphyllin I Overcomes EMT-Associated Resistance to Erlotinib in Lung Cancer Cells via IL-6/STAT3 Pathway Inhibition

Lou

Yan

Zhu

et al. 2017

Biological & Pharmaceutical Bulletin

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Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is the most important limiting factor for treatment efficiency in EGFR-mutant non-small cell lung cancer (NSCLC). Much work has linked the epithelial-mesenchymal transition (EMT) to the emergence of drug resistance, consequently, ongoing research has been focused on exploring the therapeutic options to reverse EMT for delaying or preventing drug resistance. Polyphyllin I (PPI) is a natural compound isolated from Paris polyphylla rhizomes and displayed anti-cancer properties. In the current work, we aimed to testify whether PPI could reverse EMT and overcome acquired EGFR-TKI resistance. We exposed HCC827 lung adenocarcinoma cells to erlotinib which resulted in acquired resistance with strong features of EMT. PPI effectively restored drug sensitivity of cells that obtained acquired resistance. PPI reversed EMT and decreased interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathway activation in erlotinib-resistant cells. Moreover, addition of IL-6 partially abolished the sensitization response of PPI. Furthermore, co-treatment of erlotinib and PPI completed abrogation of tumor growth in xenografts, which was associated with EMT reversal. In conclusion, PPI serves as a novel solution to conquer the EGFR-TKI resistance of NSCLC via reversing EMT by modulating IL-6/STAT3 signaling pathway. Combined PPI and erlotinib treatment provides a promising future for lung cancer patients to strengthen drug response and prolong survival.

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Section: Discussionmentioning

confidence: 99%

Section: Acquired Resistance Of the Egfr-tki Inhibitor Erlotinib In Hmentioning

confidence: 99%

Polyphyllin I Overcomes EMT-Associated Resistance to Erlotinib in Lung Cancer Cells via IL-6/STAT3 Pathway Inhibition

Lou

Yan

Zhu

et al. 2017

Biological & Pharmaceutical Bulletin

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“…These results reinforce the need for 2 nd and 3 rd generation EGFR TKIs, while taking into account existing data that suggest use of erlotinib or gefitinib beyond progression, with added chemotherapy, radiotherapy or best supportive care may improve survival 19 . Although afatinib and dacomitinib have been introduced to overcome acquired resistance, they showed limited efficacy in NSCLC with T790M and were more than 100-fold less potent in NSCLC cells with EGFR T790M mutation than in NSCLC cells with EGFR activating mutation 20 . CO-1686 is a novel covalent inhibitor that irreversibly and selectively targets both the initial activating EGFR mutations and the T790M secondary acquired resistance mutation 21 .…”

Section: Systemic Treatment In Egfr-alk Nsclc Patients: Second Line Tmentioning

confidence: 99%

Systemic treatment in EGFR-ALK NSCLC patients: second line therapy and beyond

Karachaliou

Rosell

Morales-Espinosa

et al. 2014

Expert Review of Anticancer Therapy

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Lung cancer is the most frequently diagnosed cancer and a leading cause of cancer mortality worldwide, with adenocarcinoma being the most common histological subtype. Deeper understanding of the pathobiology of non-small cell lung cancer (NSCLC) has led to the development of small molecules that target genetic mutations known to play critical roles in progression to metastatic disease and to influence response to targeted therapies. The principle goal of precision medicine is to define those patient populations most likely to respond to targeted therapies. However, the cancer genome landscape is composed of relatively few "mountains" [representing the most commonly mutated genes like KRAS, epidermal growth factor (EGFR), and anaplastic lymphoma kinase (ALK)] and a vast number of "hills" (representing low frequency but potentially actionable mutations). Low-frequency lesions that affect a druggable gene product allow a relatively small population of cancer patients for targeted therapy to be selected.

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“…It may be the cause leads to STAT3 activation upon TKI treatment. Recently, a study had been reported that lung cancer cell lines with secondary EGFR mutation showed de novo resistance to irreversible EGFR inhibitors through induction of IL-6R/JAK1/STAT3 upon afatinib treatment (41).…”

Section: Discussionmentioning

confidence: 99%

TPCA-1 Is a Direct Dual Inhibitor of STAT3 and NF-κB and Regresses Mutant EGFR-Associated Human Non–Small Cell Lung Cancers

Jing

Chen

et al. 2014

Molecular Cancer Therapeutics

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Epidermal growth factor receptor (EGFR) is a clinical therapeutic target to treat a subset of non-small cell lung cancer (NSCLC) harboring EGFR mutants. However, some patients with a similar kind of EGFR mutation show intrinsic resistance to tyrosine kinase inhibitors (TKI). It indicates that other key molecules are involved in the survival of these cancer cells. We showed here that 2-[(aminocarbonyl)amino]-5 -(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), a previously reported inhibitor of IkB kinases (IKK), blocked STAT3 recruitment to upstream kinases by docking into SH2 domain of STAT3 and attenuated STAT3 activity induced by cytokines and cytoplasmic tyrosine kinases. TPCA-1 is an effective inhibitor of STAT3 phosphorylation, DNA binding, and transactivation in vivo. It selectively repressed proliferation of NSCLC cells with constitutive STAT3 activation. In addition, using pharmacologic and genetic approaches, we found that both NF-kB and STAT3 could regulate the transcripts of interleukin (IL)-6 and COX-2 in NSCLC harboring EGFR mutations. Moreover, gefitinib treatment only did not efficiently suppress NF-kB and STAT3 activity. In contrast, we found that treatment with TKIs increased phosho-STAT3 level in target cells. Inhibiting EGFR, STAT3, and NF-kB by combination of TKIs with TPCA-1 showed increased sensitivity and enhanced apoptosis induced by gefitinib. Collectively, in this work, we identified TPCA-1 as a direct dual inhibitor for both IKKs and STAT3, whereas treatment targeting EGFR only could not sufficiently repress NF-kB and STAT3 pathways for lung cancers harboring mutant EGFR. Therefore, synergistic treatment of TPCA-1 with TKIs has potential to be a more effective strategy for cancers. Mol Cancer Ther; 13(3); 617-29. Ó2014 AACR.

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Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation

Cited by 178 publications

References 50 publications

Polyphyllin I Overcomes EMT-Associated Resistance to Erlotinib in Lung Cancer Cells <i>via</i> IL-6/STAT3 Pathway Inhibition

Polyphyllin I Overcomes EMT-Associated Resistance to Erlotinib in Lung Cancer Cells <i>via</i> IL-6/STAT3 Pathway Inhibition

Systemic treatment in EGFR-ALK NSCLC patients: second line therapy and beyond

TPCA-1 Is a Direct Dual Inhibitor of STAT3 and NF-κB and Regresses Mutant EGFR-Associated Human Non–Small Cell Lung Cancers

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