Exosomes transmit T790M mutation‐induced resistance in EGFR‐mutant NSCLC by activating PI3K/AKT signalling pathway

et al. 2020

Small

Epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase protein, and constitutive activation of EGFR has been shown to be related to cancer initiation, progression, and poor prognosis in several cancers including NSCLC. [5] The EGFR-targeted inhibitors, such as tyrosine kinase inhibitors (TKIs) (e.g., gefitinib (GEF) and erlotinib), have been developed and proved to treat advanced NSCLC, especially the lung adenocarcinoma (a subset of NSCLC). [6] Upon binding to the EGFR tyrosine kinase domain, these small molecular inhibitors can block the phosphorylation of EGFR and activation of some downstream pathways. The use of TKIs significantly increases patient prognosis and prolongs the progression-free survival with less side effect, [7] yet curative effects are usually compromised due to the occurrence of intrinsic and/or acquired resistance. [8] Activation of EGFR results in activation of several downstream signaling pathways, such as phosphatidylinositol 3-kinase/serine threonine protein kinase (PI3K/Akt) and mitogen-activated protein kinase kinase/extracellular receptor kinase (MEK/ERK) pathways, which play major roles in proliferation, survival, and drug resistance in many different cell types. [9] There is accumulating evidence that PI3K/Akt signaling is essential for mediating EGFR survival signals in NSCLC, and persistent activation of the Akt signaling has been associated with resistance to several TKIs including gefitinib in NSCLC. [10] Thus, inhibiting PI3K/Akt pathway can restore the sensitivity of NSCLC cells to TKIs and thereby reduce the resistance of NSCLC cells to TKIs therapy. [11] Indeed, recent studies reveal that the PI3K/Akt pathway inhibition along with EGFR suppression is beneficial to NSCLC treatment. [12] There results prompted us to search for an alternative formulation that can treat the TKI-resistant NSCLC effectively. Celastrol (CEL), a naturally occurring quinone methide triterpene derived from Tripterygium wilfordii, is a pleiotropic compound and has been used for treating multiple diseases including cancers. [13] A number of studies indicate that celastrol inhibits tumor cell proliferation and promotes apoptosis through significant suppression of PI3K/Akt signaling. [14] This property makes celastrol a potent component in treatment of TKI-resistant NSCLC. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the cause of high rate of mortality. The epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors are used to treat NSCLC, yet their curative effects are usually compromised by drug resistance. This study demonstrates a nanodrug for treating tyrosine-kinase-inhibitor-resistant NSCLC through inhibiting upstream and downstream EGFR signaling pathways. The main molecule of the nanodrug is synthesized by linking a tyrosine kinase inhibitor gefitinib and a near-infrared dye (NIR) on each side of a disulfide via carbonate bonds, and the nanodrug is then obtained through nanoparticle formation of the main molecule in a...

Section: Introductionmentioning

confidence: 99%

An Activatable Nano‐Prodrug for Treating Tyrosine‐Kinase‐Inhibitor‐Resistant Non‐Small Cell Lung Cancer and for Optoacoustic and Fluorescent Imaging

Xie

Zhan

et al. 2020

Small

“…Tumor-derived exosomes can be detected in the blood and body uids of patients. It has been demonstrated that exosomes can affect the therapeutic response and induce drug resistance in tumor cells [27]. Recent research has suggested that drug-resistant cells transmit drug resistance information to drug-sensitive cells through extracellular vesicles [28].…”

Section: Discussionmentioning

confidence: 99%

Elevated Exosome-derived Mirnas Predict Osimertinib Resistance in Non-small Cell Lung Cancer

Chen

et al. 2020

Preprint

Background: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations will inevitably develop drug resistance after being treated with the third-generation EGFR-tyrosine kinase inhibitor (TKI), osimertinib. In recent years, many studies have been focusing on the ability of exosomal miRNAs secreted by tumor cells to transmit resistance information. However, the mechanism of exosome-derived miRNAs in osimertinib resistance remains unexplored.Methods: We extracted and sequenced exosomes from the supernatant of the osimertinib-resistant cell line, H1975-OR, and the sensitive cell line, H1975. The results were compared with plasma exosome sequencing before and after the appearance of drug resistance in three NSCLC clinical patients treated with oral osimertinib. Exosome-derived miRNAs that had significantly increased expression levels after osimertinib resistance were screened for expanded validation in other 64 NSCLC patients.Results: Cluster analysis of the target genes revealed that exosomal miRNAs participate in osimertinib resistance mechanisms through the activation of bypass pathways (RAS-MAPK pathway abnormality and PI3K pathway activation). Exosome-derived miR-184 (p = 0.0325) and miR-3913-5p (p = 0.0169) expression levels increased significantly after the onset of osimertinib resistance. Exosomal miR-184 was correlated with lactate dehydrogenase levels (p = 0.018). Exosomal miR-3913-5p was associated with TNM stage (p = 0.045), platelet count (p = 0.024), tumor marker carcinoembryonic antigen (p = 0.045), and distant metastases (p = 0.049), especially bone metastasis (p = 0.03). In the subgroup of patients with EGFR exon 21 L858R point mutation, miR-184 (p = 0.0104) and miR-3913-5p (p = 0.0085) derived from serum exosomes had both significantly increased expression levels. In the subgroup of T790M-positive patients, miR-3913-5p derived from serum exosomes may also be a good indicator of osimertinib resistance (p = 0.013).Conclusions: The expression levels of miR-184 and miR-3913-5p derived from exosomes in the peripheral blood of NSCLC patients could be used as biomarkers to indicate osimertinib resistance.

“…This also shows that tumor-derived exosomes can be objects of liquid biopsy, re ecting the tumor burden and drug resistance. It has been proved that exosomes can affect the therapeutic response and induce drug resistance of tumor cells [29]. Recent research have suggested that drug-resistant cells transfer drug resistance to drug-sensitive cells through miRNAs and drug e ux mercury [28].…”

Section: Discussionmentioning

confidence: 99%

“…Yan Zhang[34]et al con rmed that exosomes miR-214 from Ge tinib-resistant PC9-GR could inhibit apoptosis in vitro, in vivo inhibit tumor growth and consequently gain Ge tinib resistance in EGFR-mutant lung cancer. Liu[29] et al found that miR-522-3p in exosomes from H1975 cells can increase the resistance of Ge tinib to PC9 cells.…”

mentioning

confidence: 99%

Exosomes miR-184 and miR-3913-5p are involved in Osimertinib resistance in non-small cell lung cancer patients with exon 21 L858R mutation

Chen

et al. 2020

Preprint

Background The third-generation of EGFR-TKI Osimertinib has become an important treatment option for patients with EGFR-mutant advanced NSCLC. In recent years, more and more studies have begun to pay attention to the ability of miRNAs in exosomes secreted by tumor cells to transmit resistance information. The mechanisms of exosomal miRNAs involved in Osimertinib resistance need to be studied. Methods We constructed an Osimertinib-resistant cell line H1975-OR, and collected the exosomes from the cells of the drug-resistant strain and the sensitive strain, and extracted respective RNA for sequencing. We also compared miRNAs in serum exosomes of three patients before and after resistance to Osimertinib. Enlarged samples were then validated in 64 NSCLC patients. Results Cluster analysis of target genes revealed that miRNAs in exosomes participate in Osimertinib resistance mechanisms through the activation of bypass pathways (RAS-MAPK pathway abnormality, PI3K pathway activation). MiR-184 and miR-3913-5p increased significantly in serum exosomes of patients with later Osimertinib resistance. These two miRNAs mainly cause EGFR resistance in two types of NSCLC patients, EGFR exon 21 L858R mutation and T790M positive. Conclusions Exosomes miR-184 and miR-3913-5p mainly cause Osimertinib resistance in lung cancer patients containing EGFR exon 21 L858R+ and T790M+. They are regarded as important biomarkers of third-generation EGFR-TKI resistance. This not only enriches the application of liquid biopsy in lung cancer drug resistance, but also provides a direction for future targeted drug research.