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.
Sorafenib is safe in patients with liver function impaired advanced HCC. It is effective in terms of progression-free survival and overall survival compared with best supportive care. Liver functions are the important predictive factors.
9017 Background: Osimertinib, an oral irreversible EGFR tyrosine kinase inhibitor, had promising results in patients with EGFR T790M resistance mutation of non-small-cell lung cancer (NSCLC). This study compared efficacy and toxicities of osimertinib versus docetaxel -bevacizumab as third-line treatment in EGFR T790M mutated NSCLC. Methods: In this phase 3, open-label, three-center study, we randomly assigned previously treated with TKI-chemotherapy or chemotherapy-TKI recurrent or metastatic advanced non-squamous lung cancer patients who had acquired EGFR T790M resistance mutation confirmed by tumor tissues or serum genetic test. Patients were randomly assigned in a ratio of 1:1 to receive oral osimertinib (80mg/day) or receive intravenous infusion docetaxel (75mg/m2) and bevacizumab (7.5mg/kg) until disease progression or unacceptable toxic effects. Docetaxel -bevacizumab group patients might crossover to osimertinib group after disease progression. The primary end-point of this study was progression-free survival and the secondary end-point were response rates, toxicities and OS. Results: A total of 147 patients were treated. Among them, 74 enrolled in the osimertinib group and 73 in the docetaxel-bevacizumab group. The median progression-free survival was 10.20 months and 2.95 months in the osimertinib group and docetaxel -bevacizumab group respectively (Hazard ratio 0.23; 95% confidence interval, 0.12 to 0.38; P < 0.0001). The overall response rate and disease control rate was 61.6% or 87.6% in osimertinib group 8.3% or 43.0% in docetaxel-bevacizumab group respectively. The median overall survival time was not reached. The main grade 3 or 4 toxic effects were diarrhea (2.7%) and interstitial lung disease (1.2%) in the osimertinib group and alopecia (15.1%), anorexia (12.3%), neutropenia (9.6%) and nausea (8.6%) in docetaxel -bevacizumab group. Conclusions: Response rate and progression-free survival of osimertinib group were superior to docetaxel-bevacizumab group in third-line treatment of EGFR T790M positive NSCLC. There was no survival difference between patients with EGFR 19 Del-T790M mutation and EGFR L858R-T790M mutation. Clinical trial information: NCT02959749.
N6-methyladenosine (m6A) is a common transcriptomic modification in cancer. Recently, it has been found to be involved in the regulation of non-small cell lung cancer (NSCLC) formation and metastasis. Interleukin 37 (IL-37) plays a crucial protective role in lung cancer. In our previous studies, we found that IL-37 is a potential novel tumor suppressor by inhibiting IL-6 expression to suppress STAT3 activation and decreasing epithelial-to-mesenchymal transition. Moreover, we found that treatment of IL-37 in lung cancer cells induced widespread and dynamic RNA m6A methylation. The effects of RNA m6A methylation of IL-37 treatment require further study. However, the functions of RNA m6A methylation of IL-37 treatment still await elucidation. Using MeRIP-seq and RNA-seq, we uncovered a unique m6A methylation profile in the treatment of IL-37 on the A549 cell line. We also showed the expression of m6A writers METTL3, METTL14, and WTAP and erasers ALKBH5 and FTO in A549 cells and lung cancer tissues after the treatment of IL-37. This study showed that IL-37 could lead to changes in m6A methylation level and related molecule expression level in A546 cells and may downregulate the proliferation by inhibiting Wnt5a/5b pathway in A549 cells. We conclude that IL-37 suppresses tumor growth through regulation of RNA m6A methylation in lung cancer cells.
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