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: 8643192
• 负责人: Jeffrey A. Engelman
• 金额: $ 49.69万
• 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/8643192
• 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% 的无法治愈的肺腺癌具有 KRAS 突变，尽管过去几年靶向治疗取得了令人印象深刻的进展，但针对这部分肺癌尚无批准或高效的靶向治疗。最近，我们使用综合方法，包括基因工程小鼠模型（GEMM）的研究，来检查 KRAS 突变肺癌的新型治疗策略的疗效。例如，两种有前景的治疗方法是 PI3K 抑制剂与 MEK 抑制剂的组合以及多西紫杉醇与 MEK 抑制剂的组合，两者都对 KRAS 突变肺癌具有活性。然而，这些方法对于伴有 LKB1（磷酸化 AMPK 的激酶）缺失的 KRAS 突变癌症亚群无效，这表明这些癌症可能需要独特的靶向治疗。我们发现，虽然 Kras/p53 突变型癌症（对这些疗法敏感）对 MEK-ERK 通路有很强的激活作用，但耐药性 Kras/Lkb1 突变型肺癌对该通路的参与却极少。这一发现为 Kras/Lkb1 肺癌对 MEK 抑制剂联合疗法的主要耐药性提供了机制见解。然而，最近的研究结果表明，LKB1 缺陷的癌症已经改变了代谢线路，这些代谢线路可能被针对这部分癌症特别有效的靶向治疗方法所利用。我们将加快研究步伐，解决 KRAS 突变肺癌问题。我们的目标是找到有效的、可耐受的疗法，针对具有/不具有完整 LKB1 的 KRAS 突变肺癌。我们使用全基因组遗传筛选、代谢分析和激酶抑制剂筛选来确定 LKB1 缺陷和完整 KRAS 突变肺癌的有前途的治疗策略。特别是，我们开发了一种新颖的筛选方法来识别与 MEK 抑制剂特异性结合治疗 KRAS 突变肺癌的靶标，并且已经验证了一种 MEK 和 BCL-XL 抑制剂组合，该组合在基因工程小鼠模型中表现出令人印象深刻的活性，异种移植物。由于基于 MEK 抑制剂的治疗方案可能对 LKB1 缺陷型癌症无效，因此我们开发了一种新的筛选方法来识别其抑制对 LKB1 突变型癌症具有特异性毒性的靶点，并验证了 2 个潜在靶点：DTYMK 和 CHEK1，它们调节嘧啶代谢和 DNA分别为损伤响应。我们寻求利用 GEMM 和原发性人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点，为新治疗方法的临床实施做好准备。此外，我们将询问数百个人类 KRAS 突变肺癌样本，以确定在基因工程小鼠模型中区分 Lkb1 完整和突变癌症的特征是否也能在人类小鼠模型中观察到。我们相信，成功实现这些目标将对 KRAS 突变肺癌各种亚型的信号转导和代谢线路产生重要的机制见解，并导致专门针对每个亚型的治疗方法的开发。