Inhibition of P13k and MEK Pathways in the Treatment of Lung Cancer

抑制 P13k 和 MEK 通路治疗肺癌

• 批准号: 7699517
• 负责人: Jeffrey A. Engelman
• 金额: $ 43.45万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7699517
• 关键词: 1-Phosphatidylinositol 4-Kinase; Address; Affect; Apoptosis; Cell Survival; Cells; Chemicals; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Data; Development; Disease; Disease remission; Effectiveness; Engineering; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Extracellular Signal Regulated Kinases; Foundations; Gefitinib; Genetic; Genetically Engineered Mouse; Grant; Growth; Human; IGF1R gene; KRAS2 gene; Lead; Learning; Longevity; Lung; Lung Adenocarcinoma; MAP3K3 gene; MEK inhibition; MEKs; MET Oncogene; Malignant Neoplasms; Malignant neoplasm of lung; Mammals; Mitogen-Activated Protein Kinases; Modeling; Molecular Biology; Mus; Mutant Strains Mice; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Oncogene Activation; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphatidylinositols; Phosphotransferases; Positioning Attribute; Process; Receptor Signaling; Resistance; Resistance development; Role; STK11 gene; Signal Pathway; Signal Transduction; TP53 gene; Treatment Efficacy; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; cancer therapy; cancer type; cell growth; effective therapy; follow-up; in vivo; inhibitor/antagonist; insight; mouse model; mutant; mutant mouse model; novel therapeutics; overexpression; prevent; public health relevance; research study; resistance mechanism; response; therapy resistant; treatment strategy; tumor

DESCRIPTION (provided by applicant): Although there has been substantial progress in the understanding of the molecular biology and genetics of non-small cell lung cancer (NSCLC) over the last several years, metastatic NSCLC remains incurable, and patients suffering from this disease have a median survival of ~12 months. Recently, Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have demonstrated clinical activity in patients with NSCLC. A small subset of patients has activating mutations in the EGFR kinase domain. In these patients, TKIs can produce dramatic responses. In such situations, the cancer is "addicted" to EGFR signaling. Such addicted cancers are unique in that the critical intracellular survival and growth signaling pathways such as phosphoinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) are solely regulated by EGFR. Thus, when the cancer is treated with the EGFR TKI, both PI3K and ERK signaling are turned off and the cells undergo apoptosis and cell growth arrest. Although cancers with activating EGFR mutations often have dramatic responses to EGFR TKIs, these cancers invariably develop resistance (acquired resistance), thereby limiting the clinical benefit from these drugs. Recently, we and others have identified how some NSCLCs become resistant to EGFR inhibitors. These include a secondary mutation in EGFR, T790M, amplification of the MET oncogene, and activation of IGF1R. Interestingly, regardless of the specific mechanism, when the cancer becomes resistant to EGFR TKIs, there is re-activation of these critical downstream signaling pathways in the presence of the EGFR TKI. In contrast to the subset of NSCLCs with activating EGFR mutations, most NSCLCs do not demonstrate any initial response to EGFR TKIs (de novo or primary resistance). In particular, NSCLCs with KRAS mutations are especially resistant to EGFR TKIs. In these cancers, treatment with an EGFR TKI (or any TKI) does not lead to loss of PI3K and ERK signaling, and there is no detrimental affect on cell viability or growth. Furthermore, mutations in KRAS are the most common oncogenic mutations in NSCLCs (~25% of lung adenocarcinomas), and currently, there are no targeted therapies for this subset of cancers. However, in an effort to mirror the effects of a successful TKI treatment in these KRAS mutant cancers, we have been implementing a strategy that centers on simultaneously inhibiting PI3K and MEK by combining specific chemical inhibitors of each of these kinases. We have observed dramatic effects using this combination in vivo on genetically engineered mouse models of mutant Kras and EGFR driven lung cancers. Our preliminary data suggest that successful concomitant targeting of the PI3K and MEK pathways is feasible in mammals, and leads to dramatic tumor regression in mouse models of mutant KRas and EGFR driven lung cancers. This grant centers on developing this combination therapy using genetically engineered mouse models. We also aim to learn how cancers will become resistant to this therapy so we can proactively identify strategies to increase its efficacy and prolong benefit. We are hopeful that the studies proposed in this grant will serve as the foundation for successful clinical trials implementing this treatment strategy for patients with NSCLC. PUBLIC HEALTH RELEVANCE: Understanding the roles of PI3K and MEK signaling pathways in the growth and survival of Kras and EGFR mutant lung cancers provide unique opportunities to identify rational combination targeted therapies for the treatment of this deadly disease and other types of cancer. Our proposal aims to characterize and evaluate the impact of novel therapeutic strategies that inhibit both the PI3K and MEK pathways in genetically defined de novo murine lung cancers. Results from the experiments proposed will help guide the clinical development of these combination therapies for patients with lung cancers and other cancer types.

描述（由申请人提供）：尽管过去几年对非小细胞肺癌（NSCLC）的分子生物学和遗传学的理解取得了实质性进展，但转移性 NSCLC 仍然无法治愈，患有这种疾病的患者中位生存期约为 12 个月。最近，表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），例如吉非替尼和厄洛替尼，已在非小细胞肺癌（NSCLC）患者中表现出临床活性。一小部分患者的 EGFR 激酶结构域存在激活突变。在这些患者中，TKI 可以产生显着的反应。在这种情况下，癌症对 EGFR 信号传导“上瘾”。这种成瘾性癌症的独特之处在于，关键的细胞内生存和生长信号通路，例如磷酸肌醇3激酶（PI3K）和细胞外信号调节激酶（ERK）仅由EGFR调节。因此，当用 EGFR TKI 治疗癌症时，PI3K 和 ERK 信号传导均被关闭，细胞发生凋亡和细胞生长停滞。尽管具有激活 EGFR 突变的癌症通常对 EGFR TKI 产生显着反应，但这些癌症总是会产生耐药性（获得性耐药），从而限制了这些药物的临床益处。最近，我们和其他人已经确定了一些 NSCLC 如何对 EGFR 抑制剂产生耐药性。这些包括 EGFR、T790M 的二次突变、MET 癌基因的扩增以及 IGF1R 的激活。有趣的是，无论具体机制如何，当癌症对 EGFR TKI 产生耐药性时，这些关键的下游信号通路在 EGFR TKI 存在的情况下会重新激活。与具有激活 EGFR 突变的 NSCLC 子集相反，大多数 NSCLC 并未表现出对 EGFR TKI 的任何初始反应（从头耐药或原发耐药）。特别是，具有 KRAS 突变的 NSCLC 对 EGFR TKI 特别耐药。在这些癌症中，使用 EGFR TKI（或任何 TKI）治疗不会导致 PI3K 和 ERK 信号传导丧失，并且对细胞活力或生长没有不利影响。此外，KRAS 突变是 NSCLC（约 25% 的肺腺癌）中最常见的致癌突变，目前尚无针对此类癌症的靶向治疗。然而，为了反映 TKI 治疗在这些 KRAS 突变癌症中的成功效果，我们一直在实施一项策略，重点是通过结合每种激酶的特定化学抑制剂来同时抑制 PI3K 和 MEK。我们观察到在体内使用这种组合对突变 Kras 和 EGFR 驱动的肺癌的基因工程小鼠模型产生了显着效果。我们的初步数据表明，成功同时靶向 PI3K 和 MEK 通路在哺乳动物中是可行的，并且在突变 KRas 和 EGFR 驱动的肺癌小鼠模型中导致肿瘤显着消退。这笔资助的重点是使用基因工程小鼠模型开发这种联合疗法。我们还旨在了解癌症如何对这种疗法产生耐药性，以便我们能够主动确定提高其疗效并延长益处的策略。我们希望这笔资助中提出的研究能够成为成功实施这种针对 NSCLC 患者的治疗策略的临床试验的基础。公共健康相关性：了解 PI3K 和 MEK 信号通路在 Kras 和 EGFR 突变型肺癌生长和存活中的作用，为确定治疗这种致命疾病和其他类型癌症的合理联合靶向疗法提供了独特的机会。我们的提案旨在表征和评估抑制 PI3K 和 MEK 通路的新型治疗策略对基因定义的新生小鼠肺癌的影响。所提出的实验结果将有助于指导这些针对肺癌和其他癌症类型患者的联合疗法的临床开发。