Therapeutic strategies for specific subsets of KRAS mutant lung cancers

描述（由申请人提供）：所有不可治愈的肺腺癌中有超过30%存在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，但对于这一肺癌亚组，尚无获批或高效的靶向治疗。最近，我们使用了综合方法，包括询问基因工程小鼠模型（GEMM），以检查新的治疗策略对KRAS突变肺癌的疗效。例如，两种有前景的治疗是PI 3 K抑制剂与MEK抑制剂的组合和多西他赛与MEK抑制剂的组合，两者都对KRAS突变型肺癌具有活性。然而，这些方法在伴随LKB 1（磷酸化AMPK的激酶）缺失的KRAS突变型癌症亚组中无效，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-具有强烈的MEK-ERK通路激活，但耐药Kras/Lkb 1突变型肺癌对该通路的参与程度惊人地低。这一发现为Kras/Lkb 1肺癌对MEK抑制剂联合治疗的原发性耐药性提供了机制见解。然而，最近的研究结果表明，LKB 1缺乏的癌症改变了代谢线路，这可能被靶向治疗方法所利用，这些方法在这一癌症亚组中特别有效。我们将加快研究，以解决KRAS突变型肺癌的问题。我们的目标是确定有效的，可耐受的治疗方法，将靶向KRAS突变型肺癌，无论是否有完整的LKB 1。我们已经使用全基因组遗传筛选、代谢谱分析和激酶抑制剂筛选来确定LKB 1缺陷和完整KRAS突变型肺癌的有希望的治疗策略。特别是，我们开发了一种新的筛选方法，以鉴定特异性与MEK抑制剂结合联合收割机治疗KRAS突变型肺癌的靶点，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和异种移植物中表现出令人印象深刻的活性。由于基于MEK受体的方案可能对LKB 1缺陷型癌症无效，我们开发了一种新的筛选方法来鉴定其抑制对LKB 1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CHEK 1，它们分别调节嘧啶代谢和DNA损伤反应。我们寻求使用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准备。此外，我们将询问数百个人类KRAS突变型肺癌标本，以确定在基因工程小鼠模型中区分Lkb 1完整和突变型癌症的特征是否也在其人类对应物中观察到。我们相信，这些目标的成功实现将对KRAS突变型肺癌的各种亚型的信号转导和代谢布线产生重要的机制性见解，并导致特异性靶向每个子集的治疗方法的开发。

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.