Therapeutic strategies for specific subsets of KRAS mutant lung cancers

KRAS 突变肺癌特定亚型的治疗策略

• 批准号: 8506767
• 负责人: Jeffrey A. Engelman
• 金额: $ 53.1万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-03 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506767
• 关键词: BCL1 Oncogene; Biological; Biology; CHEK1 gene; Cell Line; Clinic; Clinical; Collection; Combined Modality Therapy; DNA Damage; Data; Development; Disease; Doxycycline; Drug Targeting; Genes; Genetic; Genetic Screening; Genetically Engineered Mouse; Human; Induction of Apoptosis; Investigation; KRAS2 gene; Laboratories; Laboratory Research; Lead; Lung Adenocarcinoma; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Metabolic; Modeling; Mutate; Mutation; Oncogenes; Pathway interactions; Patients; Pharmacodynamics; Phosphotransferases; Regimen; Research; Resistance; STK11 gene; Signal Pathway; Signal Transduction; Specimen; Staging; Techniques; Technology; Therapeutic; Translating; Tumor Suppressor Proteins; Xenograft procedure; base; cancer cell; docetaxel; genome-wide; in vivo; inhibitor/antagonist; insight; kinase inhibitor; mouse model; mutant; novel; novel therapeutic intervention; novel therapeutics; public health relevance; pyrimidine metabolism; response; screening; small hairpin RNA; therapeutic development; therapeutic target

DESCRIPTION (provided by applicant): Over 30% of all incurable lung adenocarcinomas have a KRAS mutation and, despite the impressive advances in targeted therapies over past several years, no approved or highly effective targeted therapy exists for this subset of lung cancers. Recently, we have used comprehensive approaches, including interrogation of genetically-engineered mouse models (GEMMs), to examine the efficacy of novel therapeutic strategies for KRAS-mutant lung cancers. For example, 2 promising treatments are the combination of PI3K inhibitors with MEK inhibitors and docetaxel with MEK inhibitors, both which have activity in KRAS-mutant lung cancers. However, these approaches are not effective in the subset of KRAS-mutant cancers with concomitant loss of LKB1 (kinase that phosphorylates AMPK), suggesting these cancers may require unique targeted therapies. We found that, while Kras/p53-mutant cancers - which are susceptible to these therapies - had strong activation of MEK-ERK pathway, the resistant Kras/Lkb1-mutant lung cancers had strikingly minimal engagement of this pathway. This finding provides mechanistic insight to the primary resistance of Kras/Lkb1 lung cancers to combination therapies with MEK inhibitors. However, recent findings suggest that cancers with LKB1 deficiency have altered metabolic wiring that could potentially be exploited by targeted therapy approaches that would be specifically effective in this subset of cancers. We will accelerate our research to tackle the problem of KRAS-mutant lung cancers. We aim to identify potent, tolerable therapies that will target KRAS-mutant lung cancers both with/without intact LKB1. We have used genome-wide genetic screens, metabolic profiling, and kinase inhibitor screens to identify promising therapeutic strategies for LKB1-deficient and -intact KRAS-mutant lung cancers. In particular, we developed a novel screen to identify targets that specifically combine with MEK inhibitors for KRAS-mutant lung cancers, and have already validated one, an MEK and BCL-XL inhibitor combination, that demonstrated impressive activity in genetically-engineered mouse models and xenografts. Since MEK inhibitor-based regimens may not be effective against LKB1 deficient cancers, we developed a novel screen to identify targets whose inhibition is specifically toxic to LKB1-mutant cancers, and validated 2 potential targets, DTYMK and CHEK1, that regulate pyrimidine metabolism and DNA damage response, respectively. We seek to comprehensively develop these potential therapeutic targets in vivo using GEMMs and primary human lung cancer explant xenografts to prepare for clinical implementation of new therapeutic approaches. Further, we will interrogate hundreds of human KRAS-mutant lung cancer specimens to determine if features distinguishing Lkb1-intact and -mutant cancers in the genetically- engineered mouse models are also observed in their human counterparts. We are confident that successful implementation of the aims will yield important mechanistic insights into the signal transduction and metabolic wiring of the various subtypes of KRAS-mutant lung cancers and lead to development of therapeutics that specifically target each subset.

描述（由申请人提供）：超过30％无法治愈的肺腺癌具有KRAS突变，尽管过去几年来有针对性的疗法取得了令人印象深刻的进步，但对于肺癌的这一子集，尚无批准或高效的靶向疗法。最近，我们使用了全面的方法，包括对遗传学工程小鼠模型（GEMM）的询问，以检查KRAS突变肺癌的新型治疗策略的功效。例如，2种有希望的治疗方法是PI3K抑制剂与MEK抑制剂和多西他赛与MEK抑制剂的组合，这两者在KRAS突变肺癌中具有活性。但是，这些方法在KRAS突变剂癌症的子集中无效，伴随LKB1损失（磷酸化AMPK），这表明这些癌症可能需要独特的靶向疗法。我们发现，尽管Kras/p53突变癌（容易受到这些疗法的影响）具有强大的MEK-ERK途径，但耐药的KRAS/LKB1突变肺癌的肺癌的吸引力极为最小。这一发现为KRAS/LKB1肺癌与MEK抑制剂组合疗法的主要抵抗力提供​​了机械洞察力。但是，最近的发现表明，患有LKB1缺乏症的癌症改变了代谢布线，可能会通过针对性的治疗方法来利用这些接线，这些方法可能在这一癌症子集中特别有效。我们将加速研究，以解决KRAS突变肺癌的问题。我们旨在确定有效的，可耐受的疗法，这些疗法将以/没有完整的LKB1为目标Kras突变肺癌。我们已经使用了全基因组遗传筛选，代谢分析和激酶抑制剂筛选来鉴定LKB1缺陷型和-Intact Kras-Mutant-Mutant-Mutant肺癌的有希望的治疗策略。特别是，我们开发了一个新颖的屏幕，以鉴定与KRAS突变肺癌的MEK抑制剂专门结合的靶标，并已经验证了一个MEK和BCL-XL抑制剂组合，这些靶标在遗传学工艺的小鼠模型和内grapts中表现出了令人印象深刻的活性。由于基于MEK抑制剂的方案可能对LKB1缺乏癌症没有有效，因此我们开发了一个新颖的屏幕，以鉴定其抑制作用对LKB1突变癌特别有毒的靶标，并验证了2个潜在靶标，DTYMK和CHEK1，该靶标有DTYMK和CHEK1，该靶标会调节甲胺胺的代谢和DNA损伤响应。我们试图使用GEMM和原发性人类肺癌外植体异种移植物在体内全面开发这些潜在的治疗靶标，以准备新的治疗方法的临床实施。此外，我们将询问数百种人类KRAS突变肺癌标本，以确定在人类对应物中还观察到了在基因工程小鼠模型中区分LKB1-Intact和 - 突变癌的特征。我们有信心，成功实施目标将对KRAS突变肺癌的各种亚型的信号转导和代谢接线产生重要的机理见解，并导致专门针对每个子集的治疗剂的发展。