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MA 11 - Emerging Diagnostic/Biomarkers in NSCLC (ID 668)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
MA 11.07 - Exosomes-Transmitted MicroRNAs Promote EGFR-TKIs Resistance in NSCLC by Activating PI3K/AKT Signaling Pathway (ID 9446)
11:00 - 12:30 | Author(s): Jinpeng Shi
Acquired epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) resistance is a major factor contributing to targeted therapy failure in EGFR mutant non-small cell lung cancer (NSCLC), among which T790M mutation accounts for 50-60%. Emerging evidence has shown that as mediators between cells, exosomes shed by drug resistant cancer cells have the ability to horizontally transfer drug resistant phenotype to drug sensitive cells, which has been described as an important mechanism of dissemination of drug resistance. However, whether exosomes derived from EGFR-TKIs resistant NSCLC cells harboring T790M mutation could transfer resistance to sensitive cells has not been understood and the potential mechanism also remains unknown.
Exosomes were isolated from supernatants of T790M mutant NSCLC cell line (H1975) and characterized by transmission electron microscopy, nanosight and western blot. Their potential roles in mediating gefitinib resistance in sensitive cell line (PC9) were investigated in vitro and in vivo. Cell viability and the effects of exosomes on downstream signaling pathways were analyzed by CCK-8 assays and western blot. The roles of exosomes in regulating gefitinib resistance in vivo were assessed by subcutaneous transplantation tumor model in athymic nude mice. Exosomes miRNA sequencing and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) were used for exploring the underlying mechanism.
Exosomes isolated from conditioned medium of NSCLC cell lines were cup-shaped membranous vesicles with a diameter of 30-100 nm and expressed the exosomal marker CD63. Exosomes derived from H1975 could transmit gefitinib resistance to PC9 (P＜0.01) in vitro while exosomes released from PC9 cell don’t have this effect. Treatment of PC9 with H1975-derived exosomes and the inhibitor of exosomes production (GW4869) could restore gefitinib response. In vivo, the tumor volume of xenograft model of PC9 cells treated with gefitinib plus H1975-derived exosomes was significantly larger than those mice treated with gefitinib alone (P＜0.05). Furthermore, H1975 xenografts could disseminate gefitinib resistance to PC9 xenografts in the same mice. This difference disappeared by the addition of GW4869. Mechanistically, intercellular transfer of microRNAs (miR-522-3p and miR-454-3p) by exosomes disseminated gefitinib resistance through activating PI3K/AKT and MEK/ERK signaling pathways
Our findings demonstrate that EGFR-TKIs resistant cells could disseminate drug resistance to sensitive cells by intercellular transfer of exosome-transmitted microRNAs and then activating PI3K/AKT and MEK/ERK signaling pathways, which reveals a novel mechanism of acquired resistance to EGFR-TKIs in NSCLC.
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
P2.07-047 - Poor Performance Status and BRAF Mutation Predict Grade 3-5 Immune-Related Adverse Events in Pts with Advanced NSCLC (ID 10175)
09:30 - 16:00 | Author(s): Jinpeng Shi
Anti-PD1/PDL1 immunotherapy has been regarding as standard second line therapy in patients with advanced NSCLC, also as the 1[st] line setting in subpopulation with PDL1 expression of more than 50%. Anti-PD1/PDL1 drugs such as nivolumab, pembrolizumab and atezolizumab showed a durable response in those benefit population, while immune-related adverse events(irAEs) were also frequently happened. This study aimed to describe the high-risk factors for irAEs in patients with advanced NSCLC after the treatment of anti-PD1/PDL1 monoclonal antibody.
We retrospectively reviewed 72 patients with advanced non small cell lung cancers treated with PD-1/PD-L1 inhibitors (nivolumab =27, pembrolizumab =44, atezolizumab =1) in Shanghai Pulmonary Hospital from Jun 2015 to May 2017. All adverse events were assessed and classified by grades according to NCI CTCAE (version 4.0).
AEs occurred in 34 patients (47.22%). Grade 1 or 2 events included increased amylase (5), increased lipase (5), transaminitis (4), rash/ pruritus (4), xerostomia (3), nausea (3), fatigue(3), anemia (3), decreased WBC (2), hypokalemia (2) and fever, arthralgia, sense of neck stiffness, cardiac arrhythmia, decreased PLT and hypocalcemia in 1 patient each.Twelve (16.67%) patients experienced grades 3-5 events including 6 cases with ILD(grade 5=1), 3 with pleural effusions/pericardial effusions, 2 with hypothyroidism, and 1 with grade 3 fatigue. Subgroup analysis showed that patients with BRAF mutations(2 with adenocarcinomas,1 with squamous carcinomas and 1 with NSCLC) experienced significantly higher rate of serious AEs (2 ILD and 2 pleural effusions) after receiving pembrolizumab (100%vs 11.76%,p＜0.001), while it was similar according to the other driver genes mutation status (EGFR, KRAS, HER2, ALK). Patients with poor ECOG PS experienced a marginally statistically significant higher grade 3-5 AEs (p=0.063), while it was similar according to different subgroup of age (p=0.538), gender (p=0.189), histological type (p = 0.999), smoking status (0.122), lines of previous therapy (p=0.172), baseline serum LDH level(p=0.290) and CD8+ of peripheral blood (p=0.814). In addition, prior thoracic radiation has a numerical higher prone to develop ILD (23.07%vs 5.08%, p = 0.116).
Poor performance status and BRAF mutation might predict irAEs in patients with advanced NSCLC receiving PD-1/PD-L1 inhibitors, further large cohort study is warranted to investigate the high-risk factors for irAEs in patients with advanced NSCLC.