Repotrectinib Exhibits Potent Antitumor Activity in Treatment-Naïve and Solvent-Front-Mutant ROS1-Rearranged Non-Small Cell Lung Cancer

Purpose: Although first-line crizotinib treatment leads to clinical benefit in ROS1+ lung cancer, high prevalence of crizotinib-resistant ROS1-G2032R (ROS1G2032R) mutation and progression in the central nervous system (CNS) represents a therapeutic challenge. Here, we investigated the antitumor activity of repotrectinib, a novel next-generation ROS1/TRK/ALK-tyrosine kinase inhibitor (TKI) in ROS1+ patient-derived preclinical models. Experimental design: Antitumor activity of repotrectinib was evaluated in ROS1+ patient-derived preclinical models including treatment-naïve and ROS1G2032R models and was further demonstrated in patients enrolled in an on-going phase I/II clinical trial (NCT03093116). Intracranial antitumor activity of repotrectinib was evaluated in a brain-metastasis mouse model. Results: Repotrectinib potently inhibited in vitro and in vivo tumor growth and ROS1 downstream signal in treatment-naïve YU1078 compared with clinically available crizotinib, ceritinib, and entrectinib. Despite comparable tumor regression between repotrectinib and lorlatinib in YU1078-derived xenograft model, repotrectinib markedly delayed the onset of tumor recurrence following drug withdrawal. Moreover, repotrectinib induced profound antitumor activity in the CNS with efficient blood-brain barrier penetrating properties. Notably, repotrectinib showed selective and potent in vitro and in vivo activity against ROS1G2032R. These findings were supported by systemic and intracranial activity of repotrectinib observed in patients enrolled in the on-going clinical trial. Conclusions: Repotrectinib is a novel next-generation ROS1-TKI with improved potency and selectivity against treatment-naïve and ROS1G2032R with efficient CNS penetration. Our findings suggest that repotrectinib can be effective both as first-line and after progression to prior ROS1-TKI.ope

Antitumor Activity and Acquired Resistance Mechanism of Dovitinib (TKI258) in RET-Rearranged Lung Adenocarcinoma

RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore antitumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell-cycle arrest at G0-G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong antitumor effect of dovitinib was observed in an LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene-set enrichment analysis of gene expression and phosphor-kinase revealed that Src, a central gene in focal adhesion, was activated in LC-2/ad DR cells. Saracatinib, an src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src.ope

Development and evaluation of ontology-based annotation system for National Health Information Portal contents

학위논문(박사) -- 서울대학교대학원 : 간호대학 간호학과, 2023. 2. 박현애.The purpose of this study is to develop and evaluate a system that annotates health information ontology to health information contents to improve search of the National Health Information Portal, develop a health information ontology utilizing the system, and then annotate health information ontology concept to health information contents and evaluate the suitability of annotations. This study was categorized into three stages. The first step was to develop a system that creates health information ontology that connects back to health information content. In the second step, a health information ontology was developed using the system. In the last step, health information ontology concepts were annotated to health information contents. The health information ontology development and health information content annotation system received heuristic evaluation and PSSUQ evaluation from five experts. Heuristic evaluation disclosed two items with a severity level of three or higher that must be corrected due to usability problems. As a result of the PSSUQ evaluation, the average score for each item was 3.4 to 5.0 points, with the overall average score of 4.3 points. The health information ontology was developed with 3,823 concepts and 12,082 synonyms. The health information ontology was evaluated as having no errors in its structure and received an average of 4.4 points in content evaluation. Also, the evaluation confirmed that no structural error was indicated in the health information ontology, resulting in an average of 4.4 points. As a result, 14,740 ontology concepts were annotated to 3,241 contents. In the expert evaluation on annotation suitability, three concepts out of fifty concepts were evaluated as inappropriate. The significance of the health information ontology development and health information content annotation system developed in this study is to automatically annotate ontology concepts to the health information contents, whereas previous ontology development and management system was limited to ontology itself, which cannot be directly linked to the information contents utilizing available ontology information. The developed health information ontology received positive evaluations in both structure and content. The suitability of health information content annotation was created based on the principles of health information ontology and health information content annotation. Some results were improved according to the results evaluated by experts. In the future, integration between the ontology development and health information content annotation system with CMS is vital in order to apply to the content development process. In addition, it is necessary to automate the collection of user terms so that the ontology-based search function can be strengthened. In addition to providing ontology-based search, generating personalized health information contents by exploiting users search behavior is essential.본 연구의 목적은 국가건강정보포털의 검색 향상을 위해 건강정보 온톨로지를 건강정보 콘텐츠에 연계하는 시스템을 개발하여 평가하고, 그 시스템을 활용해 건강정보 온톨로지를 개발한 뒤 건강정보 콘텐츠에 건강정보 온톨로지 개념을 연계하며, 건강정보 온톨로지 및 건강정보 콘텐츠에 연계된 건강정보 온톨로지의 개념 및 용어의 연계 적합성을 평가하는 데 있다. 본 연구는 크게 세 단계로 나누어 진행하였다. 첫째 단계에서는 건강정보 콘텐츠를 활용하여 건강정보 온톨로지를 개발하고 건강정보 콘텐츠에 연계할 수 있는 시스템을 개발하였고, 둘째 단계에서는 해당 시스템을 활용하여 건강정보 온톨로지를 개발하였으며, 마지막으로 건강정보 콘텐츠에 온톨로지 개념 및 용어를 연계하였다. 건강정보 온톨로지 개발 및 건강정보 콘텐츠 연계 시스템은 5명의 전문가로부터 휴리스틱 평가와 PSSUQ 평가를 받았다. 휴리스틱 평가 결과 사용성 문제가 있어 반드시 수정되어야 하는 심각성 수준 3점 이상의 항목은 2개였다. PSSUQ 평가 결과 항목별 평균 점수는 3.4∼5.0점이었고 전체 평균 점수는 4.3점으로 나타났다. 건강정보 온톨로지는 개념 3,823개와 동의어 12,082개로 개발되었다. 겅강정보 온톨로지는 구조에 오류가 없다고 평가되었고 내용 평가에서는 평균 4.4점을 받았다. 건강정보 콘텐츠에 건강정보 온톨로지 개념을 연계한 결과 목차 단위 콘텐츠 3,241개에 온톨로지 개념 14,740개가 연계되었다. 연계 적합성에 대한 전문가 평가에서는 50개의 검색 키워드로 검색한 결과 중 3개의 키워드에서 각각 하나의 콘텐츠 연계가 부적합하다는 평가를 받았다. 본 연구에서 개발한 건강정보 온톨로지 개발 및 건강정보 콘텐츠 연계 시스템의 의의는 기존의 온톨로지 개발 및 관리 프로그램이 온톨로지에 국한되고 온톨로지가 활용될 수 있는 정보와 직접 연계하지 못한다는 한계를 보완하여 건강정보 콘텐츠와 자동으로 연계할 수 있다는 점이다. 해당 시스템을 통해 개발된 건강정보 온톨로지는 구조와 내용 두 측면에서 모두 긍정적인 평가를 받았다. 건강정보 콘텐츠 연계의 적합성은 건강정보 온톨로지와 건강정보 콘텐츠 연계 원칙에 따라 이루어졌으며 전문가들로부터 평가받은 결과에 따라 일부 결과를 개선할 수 있었다. 앞으로는 온톨로지 개발 및 건강정보 콘텐츠 연계 시스템을 콘텐츠 개발 과정에 적용할 수 있도록 CMS와 통합하는 작업이 필요하다. 또한 온톨로지 기반 검색 기능을 강화할 수 있도록 사용자 용어 수집을 자동화할 필요가 있다. 아울러 온톨로지 기반 검색 제공에 더불어 사용자의 검색 행태 기록을 활용하여 보다 더 개인화된 건강정보 콘텐츠를 제공할 필요가 있다.제 1 장 서론 1 제 1 절 연구의 필요성 1 제 2 절 연구 목적 4 제 3 절 용어의 정의 5 제 2 장 문헌 고찰 7 제 1 절 온라인 건강정보 제공 7 제 2 절 정보 시스템 개발 및 평가 9 제 3 절 온톨로지의 개발, 평가 및 활용 11 제 4 절 온톨로지 개발 및 관리 도구 13 제 3 장 연구 방법 15 제 1 절 건강정보 온톨로지 개발 및 건강정보 콘텐츠 연계 시스템 개발 15 제 2 절 건강정보 온톨로지 개발 19 제 3 절 건강정보 콘텐츠에 건강정보 온톨로지 개념 연계 23 제 4 절 연구의 윤리적 고려 27 제 4 장 연구 결과 28 제 1 절 건강정보 온톨로지 개발 및 건강정보 콘텐츠 연계 시스템 28 제 2 절 건강정보 온톨로지 개발 및 평가 결과 52 제 3 절 건강정보 콘텐츠에 건강정보 온톨로지 개념 연계 및 적합성 평가 결과 56 제 5 장 논의 60 제 1 절 건강정보 온톨로지 개발 및 건강정보 콘텐츠 연계 시스템 60 제 2 절 건강정보 온톨로지 61 제 3 절 건강정보 콘텐츠에 건강정보 온톨로지 개념 연계 62 제 6 장 결론 및 제언 64 참 고 문 헌 66박

Development and application of hypertension management mobile system based on clinical practice guidelines

학위논문 (석사)-- 서울대학교 대학원 : 간호학과, 2014. 8. 박현애.본 연구의 목적은 고혈압환자의 자가 관리를 돕기 위해 임상 실무지침에서 지식을 추출하여 고혈압 환자에게 맞춤형 관리를 제공하는 모바일 어플리케이션을 개발하고 이를 적용하여 평가하는데 있다. 어플리케이션의 개발은 계획, 분석, 설계, 구현, 평가의 단계로 이루어졌다. 계획 단계에서는 고혈압 관리 임상실무지침을 선정하여 관리 내용을 추출하고 어플리케이션 개발 영역을 정의하였다. 선정된 내용을 바탕으로 데이터, 프로세스, 인터페이스 영역을 구분해 분석, 설계, 구현 단계를 진행하였다. 데이터 영역에서는 분석단계에서 지식에 포함된 데이터를 추출한 후 데이터사전을 개발하고, 설계단계에서 데이터간의 관계를 개체관계다이어그램으로 표현하고, 구현단계에서 데이터베이스로 구현하였다. 프로세스 영역에서는 분석단계에서 임상실무지침에 포함된 규칙을 분석하고, 설계단계에서 알고리즘으로 구조화하고, 구현단계에서 코딩을 하였다. 데이터 영역과 프로세스 영역의 분석 단계에서 도출된 데이터와 규칙을 통합하여 고혈압 관리 온톨로지와 고혈압 관리 맞춤형 권고안을 개발하였다. 인터페이스 영역에서는 분석 단계에서 어플리케이션의 필수 기능을 분석하여 유스케이스 다이어그램으로 제작하고 이를 바탕으로 설계단계에서 UI(User Interface)를 설계하여 구현단계에서 코딩 하였다. 평가 단계에서는 지식베이스의 정확도평가와 모바일 휴리스틱 평가를 시행하였고, 평가 결과를 바탕으로 시스템을 수정하였다. 어플리케이션의 적용은 고혈압 환자를 대상으로 4주 동안 고혈압 관리 어플리케이션을 사용하도록 한 뒤 지각된 유용성과 사용자 만족도, 사전 사후 복약 순응도를 조사하였다. 그 결과 지각된 유용성은 5점 만점에 3.7점이었으며 사용자 만족도는 혈압기록기능 4.3점, 복약기록기능 3.8점, 기록전송기능 3.1점, 알림 기능 3.2점, 권고안 제공 기능 3.4점, 약물정보 확인기능 3.8점으로 나타났다. 모리스키도구 수정본으로 평가한 복약 순응도는 어플리케이션 사용 후 유의하게(p=.001) 향상되었다. 본 연구에서 개발한 어플리케이션을 적용하여 복약 순응도의 향상이 확인되었으나 앞으로 환자 결과 측면에서 더 직접적으로 약물 복용율, 생활습관의 변화 및 혈압의 변화를 측정하여 시스템 효과를 평가하는 연구가 필요하다.In this study, a clinical practice guideline-based hypertension management mobile application was developed and evaluated. The application was developed according to Web-Roadmap methodology from planning, analysis, design, implementation to evaluation. In the planning phase, development process was determined and hypertension management clinical practice guidelines were selected. Data, process and interface domains were separately analyzed, designed and implemented. In data domain, data were extracted from the clinical guidelines and expressed as data dictionary. Relations of data entities were expressed by entity-relation diagram and coded into a database. In process domain, rules were extracted from clinical practice guidelines and organized as algorithms. Algorithms then were coded. Hypertension management ontology and tailored recommendations were developed by linking data with rules. In interface domain, functions were extracted and presented as a use-case diagram. System interface was designed and coded. In evaluation phase, tailored recommendations were tested their accuracy and mobile heuristics were evaluated. Perceived usefulness and user satisfaction were surveyed with 19 patients. Pre-post medication adherence were measured with 29 hypertension patients before and after using the application for 4 weeks. As a result, perceived usefulness score was 3.7 of 5. User satisfaction score with blood pressure recording, medication recording, data sending, alarming, recommending and educating medicine information functions were respectively 4.3, 3.8, 3.1, 3.2, 3.4 and 3.8 of 5. Medication adherence measured by Modified-Morisky scale was significantly improved(p=.001) after usage of the application. Even though the clinical practice guideline based hypertension management mobile application proved to be effective in medication adherence, a further study is needed to study direct measure of medication adherence, lifestyle change and blood pressure change.I. 서 론 1 1. 연구의 필요성 1 2. 연구의 목적 3 3. 용어의 정의 4 II. 문헌 고찰 6 1. 고혈압 관리 임상실무지침 6 2. 컴퓨터 해석 가능 형태의 임상실무지침 8 3. 모바일 헬스케어 어플리케이션 10 4. 복약 순응도 12 III. 연구의 틀 15 1. 연구의 개념모델 15 IV. 연구 방법 19 1. 연구 설계 19 2. 고혈압 관리 어플리케이션 개발 19 3. 고혈압 관리 어플리케이션 적용 26 4. 연구의 윤리적 고려 29 V. 연구 결과 30 1. 고혈압 관리 어플리케이션 개발 30 2. 고혈압 관리 어플리케이션 적용 62 VI. 논의 68 1. 고혈압 관리 어플리케이션 개발 68 2. 고혈압 관리 어플리케이션 적용 70 3. 연구의 제한점 72 VII. 결론 및 제언 73 참고문헌 74Maste

소비자의 술집 평가기준 척도개발에 관한 연구

이 논문은 울산광역시의 울산대학교 학생 200명을 대상으로 하여 소비자의 술집평가기준에 관한 척도를 개발하였다. 대학생 소비자가 술집을 선택할 때 중요하게 고려해야 할 평가기준으로 25개 문항을 선정하였다. 25개 문항을 요인분석 한 결과 8개의 요인이 추출되었다. 각 요인에 속하는 문항들의 기여도를 알아보기 위하여 요인에 포함된 모든 문항을 더한 점수를 종속변수로 하고 각 문항의 점수를 독립변수로 하여 단계별 회기분석을 함으로써 설명력의 증가분을 검토하였다. 마지막으로 척도의 신뢰도를 알아보기 위하여 25개 문항의 상관관계를 검토하였고, 요인별 신뢰도계수를 구하였다. 이러한 과정을 거친 결과 이 논문에서 개발한 척도는 신뢰도가 높다는 사실을 경험적으로 입증되었다.This research developed a scale to measure consumers' evaluative criteria about a drinking house. The data was collected from 200 college students in Ulsan. 25 items were selected as the criteria for the choice of drinking house. The factor analysis was used to identify the 8 sub-dimensions of consumers' evaluative criteria about the favorite drinking house. The stepwise multiple regression was used to predict the explanatory power of each items included in each factors. The Pearson's product moment correlation of inter item and reliability coefficient was calculated. This measure was found to be reliable throughout above mentioned several analyses.이 논문은 울산광역시의 울산대학교 학생 200명을 대상으로 하여 소비자의 술집평가기준에 관한 척도를 개발하였다. 대학생 소비자가 술집을 선택할 때 중요하게 고려해야 할 평가기준으로 25개 문항을 선정하였다. 25개 문항을 요인분석 한 결과 8개의 요인이 추출되었다. 각 요인에 속하는 문항들의 기여도를 알아보기 위하여 요인에 포함된 모든 문항을 더한 점수를 종속변수로 하고 각 문항의 점수를 독립변수로 하여 단계별 회기분석을 함으로써 설명력의 증가분을 검토하였다. 마지막으로 척도의 신뢰도를 알아보기 위하여 25개 문항의 상관관계를 검토하였고, 요인별 신뢰도계수를 구하였다. 이러한 과정을 거친 결과 이 논문에서 개발한 척도는 신뢰도가 높다는 사실을 경험적으로 입증되었다.This research developed a scale to measure consumers' evaluative criteria about a drinking house. The data was collected from 200 college students in Ulsan. 25 items were selected as the criteria for the choice of drinking house. The factor analysis was used to identify the 8 sub-dimensions of consumers' evaluative criteria about the favorite drinking house. The stepwise multiple regression was used to predict the explanatory power of each items included in each factors. The Pearson's product moment correlation of inter item and reliability coefficient was calculated. This measure was found to be reliable throughout above mentioned several analyses

A Study on the Condition of Using the Study Skills and the Need of Study Skills Training

본 연구는 우리나라 대학생의 학습기술 활용 실태 및 학습 기술 훈련에 대한 요구를 밝히는 데에 목적을 두었다. 이를 위하여 먼저, 성별, 학년, 학문계열에 따른 학습 기술의 활용 실태의 차이를 확인하고, 다음으로, 학습기술의 하위요인별로 훈련에 대한 요구의 정도를 확인하였다. 연구결과는 다음과 같다. 첫째, 대학생들의 학습기술 활용 실태를 조사한 결과, 자기관리 기술을 제외한 학습기술의 모든 하위영역에서 남학생이 여학생보다 높게 나타났다. 또한, 전공 계열 간 학습기술의 차이에 있어, 과제해결 기술 영역에서 인문사회계열보다 이공계열의 과제해결 기술 점수가 더 높은 것으로 나타났다. 그리고 모든 학습기술의 하위요인들 중 자기관리와 정보처리, 시험치기 그리고 전체 학습기술 점수는 1학년에서 3학년까지 감소하는 것으로 나타났으며, 과제해결과 읽기, 수업청강 기술은 학년이 높아짐에 따라 감소하는 것으로 밝혀졌다. 둘째, 대학생들의 학습기술 훈련에 대한 요구를 조사한 결과, 자기관리 기술 중 '시간관리훈련', 수업청강 기술 중 '강의에 집중하기 훈련', 과제해결 기술 중 '과제해결 방안탐색 훈련', 시험치기 기술 중 '시험치는 요령과 심리적 대처기술 훈련', 정보처리 기술 중 '효율적인 정보처리 기능의 활용을 위한 내적 심리상태 유지 훈련', 그리고 읽기 기술 중 '핵심개념 파악하기 훈련'에 대한 요구가 가장 높은 것으로 밝혀졌다. The purpose of this study was to examine the condition of using the study skills and the need of study skills training of the Korean university students. For this study, the condition differences of using the study skills in gender, grades and majors and the level of the need for the study skills training on subparts of the study skills were investigated. A sample of 598 Korean university students were considered. Subjects were classified by gender, grades and major. Learning and Study Strategies Inventory for University students administered to the subjects along with a researcher's developing Study Skills Training Needs questionnaire. Data were analyzed using the Statistical Package for the Social Sciences (SPSS Version 12.0). T-test and ANOVA analysis procedures were employed. Results indicated that in the condition of using the study skills (1) there were significant differences in the ages except a self-management skill. These differences were bigger for the male students than for the female students. (2) there were significant differences between the engineering majors and humanity/social science majors. The students' problem-solving skill scores in humanity/social science majors were higher than those in the engineering majors. However, no significant differences was found in the other majors. (3) there were significant differences in the grades for all the subparts of the study skills. We found that Self-management, information-processing and test-taking skills were reduced from freshman to junior, but problem-solving, reading and lesson-listening skills were improved from freshman to senior. In the level of the need for the study skills training, the results show that (1) time-management training among self-management skills, concentration training among lesson-listening skills, problem-finding training among problem-solving skills, test-taking and anxiety relaxation training among test-taking skills, psychological retention training for the effective information-processing use among information-processing skills, and main idea finding training among reading skills were more needed than any other skills training by these Korean university students

ERK-dependent IL-6 autocrine signaling mediates adaptive resistance to pan-PI3K inhibitor BKM120 in head and neck squamous cell carcinoma

Hyperactivation of phosphatidylinositol 3-kinase (PI3K) pathway occurs frequently in head and neck squamous cell carcinoma (HNSCC). However, clinical outcomes of targeting the PI3K pathway have been underwhelming. In present study, we investigated the resistant mechanisms and potential combination therapeutic strategy to overcome adaptive resistance to PI3K inhibitor in HNSCC. Treatment of NVP-BKM120, a pan-PI3K inhibitor, led to upregulation of interleukin-6 (IL-6) and subsequent activation of either extracellular signal-regulated kinase (ERK) or signal transducers and activators of transcription 3 (STAT3), causing modest antitumor effects on the growth of HNSCC cells. Blockade of autocrine IL-6 signaling with siRNA or neutralizing antibody for IL-6 receptor (IL-6R) completely abolished NVP-BKM120-induced activation of ERK and STAT3 as well as expression of c-Myc oncogene, which resulted in enhanced sensitivity to NVP-BKM120. Moreover, when compared with a pharmacologic inhibitor or silencing of STAT3, trametinib, a MEK inhibitor, in combination with NVP-BKM120 yielded more potent anti-proliferative effects by inhibiting S phase transition, arresting cells at G0/G1 phase, and downregulating IL-6 and c-Myc expression. Furthermore, as compared with either agent alone, combination of NVP-BKM120 with trametinib or tocilizumab, a humanized anti-IL-6R antibody, significantly suppressed tumor growth in NVP-BKM120-resistant patient-derived tumor xenograft (PDTX) models, which was also confirmed in PDTX-derived cell lines. Collectively, these results suggested that IL-6/ERK signaling is closely involved in adaptive resistance of NVP-BKM120 in HNSCC cells, providing a rationale for a novel combination therapy to overcome resistance to PI3K inhibitors.restrictio

Establishment of a Conditional Transgenic Mouse Model Recapitulating EML4-ALK-Positive Human Non-Small Cell Lung Cancer

BACKGROUND: Anaplastic lymphoma receptor tyrosine kinase gene (ALK) fusion is a distinct molecular subclassification of NSCLC that is targeted by anaplastic lymphoma kinase (ALK) inhibitors. We established a transgenic mouse model that expresses tumors highly resembling human NSCLC harboring echinoderm microtubule associated protein like 4 gene (EML)-ALK fusion. We aimed to test an EML4-ALK transgenic mouse model as a platform for assessing the efficacy of ALK inhibitors and examining mechanisms of acquired resistance to ALK inhibitors. METHODS: Transgenic mouse lines harboring LoxP-STOP-LoxP-FLAGS-tagged human EML4-ALK (variant 1) transgene was established by using C57BL/6N mice. The transgenic mouse model with highly lung-specific, inducible expression of echinoderm microtubule associated protein like 4-ALK fusion protein was established by crossing the EML4-ALK transgenic mice with mice expressing Cre-estrogen receptor fusion protein under the control of surfactant protein C gene (SPC). Expression of EML4-ALK transgene was induced by intraperitoneally injecting mice with tamoxifen. When the lung tumor of the mice treated with the ALK inhibitor crizotinib for 2 weeks was measured, tumor shrinkage was observed. RESULTS: EML4-ALK tumor developed after 1 week of tamoxifen treatment. Echinoderm microtubule associated protein like 4-ALK was strongly expressed in the lung but not in other organs. ALK and FLAGS expressions were observed by immunohistochemistry. Treatment of EML4-ALK tumor-bearing mice with crizotinib for 2 weeks induced dramatic shrinkage of tumors with no signs of toxicity. Furthermore, prolonged treatment with crizotinib led to acquired resistance in tumors, resulting in regrowth and disease progression. The resistant tumor nodules revealed acquired ALK G1202R mutations. CONCLUSIONS: An EML4-ALK transgenic mouse model for study of drug resistance was successfully established with short duration of tumorigenesis. This model should be a strong preclinical model for testing efficacy of ALK TKIs, providing a useful tool for investigating the mechanisms of acquired resistance and pursuing novel treatment strategies in ALK-positive lung cancer.restrictio