We demonstrated that in vitro drug responses in patient-derived organoids (PDOs) are correlated to clinical responses to targeted therapies in individual patients with advanced lung adenocarcinoma and PDOs can be used to identify effective anti-cancer therapies for novel molecular targets. PDOs recapitulated progression-free survival and objective responses of NSCLC patients receiving clinically approved targeted agents. PDOs also predicted activity of therapeutic strategies under clinical investigation. YUO-071 harboring an EGFR exon 19 deletion and a BRAF G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an EGFR L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to demonstrate preclinical efficacy of poziotinib against ERBB2 exon 20 insertions and pralsetinib against RET-fusions. Our findings suggest utility of PDOs in clinical decision making and development of therapeutic strategies.

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The aim of this study was to provide descriptive information on meal and snack patterns and to investigate snacks in relation to energy intake and food choice according to the meal patterns of employed people in Korea. 683 employed people (292 males, 391 females) were interviewed to collect one day dietary data by using 24-h dietary recall. A recorded day was divided into 3 meal and 3 snack periods by the respondent's criteria and the time of consumption. To analyze the eating pattern participants were divided as the more frequent snack eaters (MFSE) and the less frequent snack eaters (LFSE). They were also categorized into 6 groups according to the frequency of all eating occasions. The common meal pattern in nearly half of the subjects (47.6%) was composed of three meals plus one or two snacks per day. A trend of an increasing the number of snacks in between main meals emerges, although the conventional meal pattern is still retained in most employed Korean adults. Women, aged 30-39, and urban residents, had a higher number of being MFSE than LFSE. Increasing eating occasions was associated with higher energy, protein, and carbohydrate intakes, with the exception of fat intakes. 16.8% of the total daily energy intake came from snack consumption, while the 3 main meals contributed 83.2%. Energy and macronutrient intakes from snacks in the MFSE were significantly higher than the LFSE. Instant coffee was the most popular snack in the morning and afternoon, whereas heavy snacks and alcohol were more frequently consumed by both of the meal skipper groups (≤2M+2,3S and ≤2M+0,1S) in the evening. In conclusion, meal pattern is changing to reflect an increase of more snacks between the three main meals. Meal and snack patterns may be markers for the energy and macronutrient intakes of employed people in Korea.

The purpose of this study was to compare the beverage consumption by gender and season in elementary school children and to investigate the role of beverage consumption patterns on their daily nutrient intakes and BMIs. Beverage consumption and dietary energy intake in 160 elementary school students in the Gyeongnam area were measured by a beverage frequency and quantity questionnaire and three 24-hour dietary recalls during winter and summer. The number of drinking moments per month, the amounts of beverage per day, and the energy from beverage consumption were not different between winter and summer. In summer, the contribution of energy from sweetened beverage to the daily energy intake in girls accounted for 13.5% which was significantly higher compared to 7.7% in boys. In girls, the consumption of health beverage showed a significant correlation with various nutrient intakes in winter. Meanwhile, the sweetened beverage intake was negatively correlated with energy, protein, vitamin A and niacin intake in summer. Consumption of most of the beverages, including sweetened beverages, were not related with BMI in both sexes and both seasons, except functional drinks which were related with BMI in boys in winter.

Background: EGFR-TKI is an established first-line therapy for NSCLC with activating EGFR mutations. Osimertinib, third-generation EGFR TKI, was investigated as a first-in-class drug, but lazertinib(YH25448) was also reported as an outstanding drug which had similar efficacy as osimertinib. Nevertheless, acquired resistance is inevitably developed by third-generation EGFR-TKIs in clinic. Even though EGFR C797S mutation has been identified as a major resistant mechanism, the remaining resistance mechanisms to these TKIs are largely unknown. Methods: To explore the mechanism of resistance to lazertinib, we firstly established drug-resistant cells to lazertinib in vitro using four NSCLC cells including the patient-derived cell line (PDC), patient-derived tumor xenograft cell line (PDTC), and ATCC cell lines. To analyze the changes in global genetic alterations and gene expression of established lazertinib-resistant cell lines(YH1R), whole exome sequencing (WES) and RNA sequencing (RNA-seq) were performed. The effect of EGFR/BRAF fusion was investigated in vitro using established YH1R cell line and various patient-derived tumor xenograft samples. Western blot study was used to investigate EGFR and MAPK cascade signaling pathway. We evaluated antitumor activity of MEK inhibitor and lazertinib combination treatment in lazertinib-resistant NSCLC cells with EGFR/BRAF fusion in vitro and in vivo. Results: RNA-seq data revealed a novel EGFR/BRAF fusion transcript (EGFR Exon 19-BRAF Exon 9, in-frame fusion) in lazertinib-resistant PC9GR_YH1R. The fusion gene consisted of EGFR (Exon 1-19) portion and BRAF kinase domain (Exon 9-18). The EGFR/BRAF fusion mRNA and protein were specifically upregulated in PC9GR_YH1R compared to parental cells. Intriguingly, we detected the EGFR/BRAF fusion gene expression in patient-derived xenografts (YHIM-1045 and YHIM-1035) obtained from patients who experienced acquired resistance to lazertinib. Compared with treatment with either single agent, combination treatment of lazertinib and MEK inhibitor, trametinib or selumetinib, was significantly effective at inhibiting cell proliferation as well as EGFR signaling pathways in PC9GR_YH1R in vitro and in vivo. Conclusion: We found a novel EGFR/BRAF fusion gene, as a key driver of acquired resistant mechanism of lazertinib, in NSCLC cell lines and patient-derived xenografts with acquired resistance to lazertinib. Combination treatment of lazertinib and MEK inhibitor showed a strong antitumor effect in lazertinib-acquired resistant NSCLCs, indicating that the combination therapy of EGFR and MEK inhibitors might be a promising therapeutic option for overcoming lazertinib-acquired resistant NSCLC patients in clinic. Citation Format: Seo-Yoon Jeong, Jiyeon Yun, San-Duk Yang, Soo-Hwan Lee, Sangbin Lim, Seok-Young Kim, Min Hee Hong, Sun Min Lim, Hye Ryun Kim, Hye Ryun Kim, Byoung Chul Cho. BRAF and EGFR fusion as a novel mechanism of resistance mechanism to Lazertinib, 3rd- generation EGFR-TKI, in EGFR-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1106.