Increased Expression of IRE1α Associates with the Resistant Mechanism of Osimertinib (AZD9291)-resistant non-small Cell Lung Cancer HCC827/OSIR Cells

Tang, Zhenghai; Su, Min‐Xia; Guo, Xia; Jiang, Xiaoming; Jia, Lin; Chen, Xiuping; Lu, Jin‐Jian

doi:10.2174/1871520617666170719155517

Cited by 23 publications

(23 citation statements)

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“…Osimertinib for second-line treatment in EGFR T790M positive NSCLC was associated with a response rate of 61% and PFS of 9.6 months [ 13 ]. But the mechanism of osimertinib resistance is much complicated [ 6 , 7 ]. Third-generation EGFR-TKIs (WZ 4002, rociletinib, osimertinib) have pyrimidine structure and covalent bond with EGFR Cys797 at ATP binding pocket.…”

Section: Discussionmentioning

confidence: 99%

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Mutational Profiling of Non-Small-Cell Lung Cancer Resistant to Osimertinib Using Next-Generation Sequencing in Chinese Patients

Nie¹,

Jiang

Zhang

et al. 2018

BioMed Research International

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Purpose To identify the somatic mutated genes for optimal targets of non-small-cell lung cancer after resistance to osimertinib treatment. Patients and Methods Study patients all had advanced lung adenocarcinoma and acquired resistance to osimertinib as a second- or third-line treatment. These patients had harboring EGFR T790M mutation before osimertinib treatment, which was confirmed by Amplification Refractory Mutation System (ARMS) PCR or Next-Generation Sequencing (NGS). After resistance to osimertinib treatment, tumor tissue was collected by core needle biopsy. DNA was extracted from 15 × 5 um sliced section of formalin-fixed paraffin-embedded (FFPE) material and NGS was done. The genetic changes were analyzed. Results A total of 9 Chinese patients were studied, 5 females and 4 males, age 51–89 years. After progression with osimertinib treatment, core needle biopsy was performed and next-generation sequencing was performed. Nine patients had harboring 62 point mutations, 2 altered gene copies, 2 amplifications, and 1 EML4-ALK gene fusion. No MET or HER2 amplification was found in this cohort study. Nine patients still maintained initial EGFR 19 del or L858R activating mutations, while 7 of them kept EGFR T790M mutations. Among the 7 patients, 5 had secondary EGFR C797S and/or C797G mutations, which all happened in the same allele with T790M mutation. All patients were treated with targets therapies, chemotherapy, or best supportive care (BSC) in accordance with NGS genetic results and patients' performance status; 7 of them are still alive and 2 of them died of disease progression at last follow-up. Conclusions EGFR C797S/G mutation and the same one presented on the same allele with EGFR T790M mutation were the most common mutation feature and played a key role in resistance to osimertinib in Chinese patients with NSCLC. Tumor cells losing T790M mutation and maintaining EGFR activating mutation might benefit from first-generation EGFR-TKI treatment.

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Section: Discussionmentioning

confidence: 99%

“…Phenotype transformation, EGFR new point mutation, pathways activation, or targets loss were the strongest possibilities. Most studies reported that C797S mutation happened in 20–30% of patients after osimertinib initiation [ 6 , 7 ]. The EGFR C797S mutation conferred resistance to third-generation EGFR-TKI.…”

Section: Introductionmentioning

confidence: 99%

Mutational Profiling of Non-Small-Cell Lung Cancer Resistant to Osimertinib Using Next-Generation Sequencing in Chinese Patients

Nie¹,

Jiang

Zhang

et al. 2018

BioMed Research International

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“…26 ERN2 also activates serine/threonine-protein kinase and participates in the response to EGFR-TKIs. 27,28 Our study observed that the expression of EEF1A2 was downregulated in patients with MLNM harboring EGFR 19Del mutations compared with those patients without MLNM, and conversely upregulated in patients with MLNM harboring EGFR L858R mutations, whereas the expression of ERN2 was upregulated in patients with EGFR 19Del mutations and downregulated in those with EGFR L858R mutations. The expression of ERN2 was verified with quantitative RT-PCR in these 10 patients and found to be consistent with the results from transcriptome sequencing.…”

Section: Discussionmentioning

confidence: 64%

EEF1A2 and ERN2 could potentially discriminate metastatic status of mediastinal lymph node in lung adenocarcinomas harboring EGFR 19Del/L858R mutations

Xia

Wang

et al. 2020

Thoracic Cancer

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Background: Early data has indicated that EGFR 19Del mutation and EGFR L585R mutation are two different types of non-small cell lung cancer (NSCLC). However, how the different molecular mechanisms participate in the process of mediastinal lymph node metastasis (MLNM) in lung adenocarcinoma (LA) harboring EGFR 19Del and EGFR L858R mutation remains unknown. We thus explored the genes responsible for MLNM in LA with EGFR 19Del or L858R mutation. Methods: We performed transcriptome sequencing and bioinformatics analysis from 10 patients with LA resection specimens of primary tumors. Quantitative reverse transcription-polymerase chain reaction was used to validate gene expressions. Results: There were 69 mRNAs upregulated and 100 mRNAs downregulated in five samples with MLNM compared with samples without MLN metastasis. EEF1A2 and ERN2 were observed exhibiting different expression patterns in EGFR 19Del and EGFR L858R samples with MLNM. In samples harboring EGFR 19Del mutation, the expression of EEF1A2 gene in samples with MLNM was significantly lower compared with samples without MLN metastasis, and in samples with EGFR L858R, it was significantly higher in samples with MLNM. The expression pattern of ERN2 was opposite to EEF1A2. In addition, several other genes including SLC6A11, IGHV3-48, IGHV3-43, DUSP9, and HOXA9 were also shown to be associated with invasion and metastasis and exhibited an expression pattern similar to EEF1A2 and ERN2 in EGRF 19Del and L858R mutation tumors. Conclusions: EEF1A2 and ERN2 were for the first time observed exhibiting distinct expression patterns in MLNM in lung adenocarcinomas harboring EGFR 19Del and EGFR L858R mutation by interindividual DEGs analysis.

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“…TGF-β1 activates ERK signaling, which is required for TGF-β1-mediated EMT in vitro 63 67 . However, IRE1α overexpression was associated with the resistant mechanism to osimertinib in NSCLC HCC827/OSIR Cells 68 . Similarly, several studies have shown that IRE1α plays a contradictory role in colon cancer cells [69][70][71][72] .…”

Section: Discussionmentioning

confidence: 92%

Calreticulin Promotes EMT in Pancreatic Cancer via Mediating Ca2+ Dependent Acute and Chronic Endoplasmic Reticulum Stress

Sheng

Wang

Tang

et al. 2020

Preprint

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Background: Our previous study showed that calreticulin (CRT) promoted EGF-induced epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC) via Integrin/EGFR-ERK/MAPK signaling. We next investigated the novel signaling pathway and molecular mechanism involving the oncogenic role of CRT in PC development. Methods: We investigated the potential role and mechanism of CRT in regulating Ca2+ dependent acute and chronic endoplasmic reticulum stress (ERS)-induced EMT in PC in vitro and vivo.Results: Thapsigargin (TG) induced acute ERS via increasing intracellular free Ca2+ in PC cells, which was reversed by CRT silencing. Additionally, CRT silencing inhibited TG-induced EMT in vitro by reversing TG-induced changes of the key proteins in EMT signaling (ZO-1, E-cadherin and Slug) and ERK/MAPK signaling (pERK), and inhibiting TG-promoted cell invasion and migration. Meanwhile, CRT was coimmunoprecipitated with inositol-requiring enzyme 1α (IRE1α, one of the key stressors in unfolded protein response) in vitro and its silencing led to the chronic ERS via upregulating IRE1α but independent of X-box-binding protein 1 (XBP1). Moreover, CRT silencing inhibited IRE1α silencing-promoted EMT, including inhibiting the activation of EMT and ERK/MAPK signaling and the promotion of cell mobility. In addition, CRT silencing decreased subcutaneous tumor size and distant liver metastasis in vivo. Furthermore, a negative relationship between CRT and IRE1α was observed in vivo and in clinical PC samples, which coordinately promoted the advanced clinical stages and poor prognosis of PC patients. Conclusions: CRT promoted EMT in PC via mediating Ca2+ dependent TG-induced acute ERS and IRE1α-mediated chronic ERS via Slug and ERK/MAPK signaling.

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Increased Expression of IRE1α Associates with the Resistant Mechanism of Osimertinib (AZD9291)-resistant non-small Cell Lung Cancer HCC827/OSIR Cells

Abstract: An increased expression of IRE1α may be one of the resistant mechanisms for OSI-resistant NSCLC.

Cited by 23 publications

References 0 publications

Mutational Profiling of Non-Small-Cell Lung Cancer Resistant to Osimertinib Using Next-Generation Sequencing in Chinese Patients

Mutational Profiling of Non-Small-Cell Lung Cancer Resistant to Osimertinib Using Next-Generation Sequencing in Chinese Patients

EEF1A2 and ERN2 could potentially discriminate metastatic status of mediastinal lymph node in lung adenocarcinomas harboring EGFR 19Del/L858R mutations

Calreticulin Promotes EMT in Pancreatic Cancer via Mediating Ca2+ Dependent Acute and Chronic Endoplasmic Reticulum Stress

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