Targeting undruggable RAS for cancer treatment

靶向不可成药的 RAS 进行癌症治疗

• 批准号: 10465051
• 负责人: CHANNING J. DER
• 金额: $ 90万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10465051
• 关键词: Adherence; Automobile Driving; Autophagocytosis; Award; Biochemistry; Biology; Cancer Etiology; Cessation of life; Colorectal Cancer; Defect; Dependence; Development; Enzymes; Frequencies; Fruit; Glycolysis; Goals; Growth; Human; Impairment; KRAS2 gene; MYC Family Protein; MYC gene; Mainstreaming; Malignant Neoplasms; Malignant neoplasm of pancreas; Metabolic; Mitochondria; Mutation; Pancreatic Ductal Adenocarcinoma; Play; Protein Kinase; Research; Research Personnel; Research Support; Resistance; Risk; Role; Signal Transduction; Time; anticancer research; base; cancer therapy; clinical efficacy; high reward; high risk; member; mutant; neglect; novel; ras Oncogene; ras Proteins; targeted treatment; therapeutically effective; tumor metabolism

PROJECT SUMMARY/ABSTRACT My Outstanding Investigator Award (OIA) research plan will build on themes developed during my more than three decades of RAS research, pursuing directions generally ignored by the RAS field and by the NCI RAS Initiative, to make “undruggable” RAS druggable. I was a member of the research team that made the initial identification of activated RAS oncogenes in human cancers. Since that discovery, my research has centered on understanding the basic biochemistry, signaling and biology of RAS proteins, with the long-term goal of utilizing that information for the development of anti-RAS cancer therapies. My research focuses on pancreatic ductal adenocarcinoma (PDAC), a cancer where effective targeted therapies remain to be found. With a 95% KRAS mutation frequency and with substantial experimental evidence that “correcting” the KRAS defect will significantly impair PDAC growth, PDAC is arguably the most RAS-addicted cancer. The OIA supports research that “take[s] greater risks, [is] more adventurous”. Based on our unpublished findings from studies initiated 3-4 years ago and just now coming into fruition, I have identified four new high risk / high reward research directions. First, despite the well-established interdependency between the RAS and MYC oncogenes in driving cancer growth, targeting MYC as an anti-KRAS strategy is not widely considered. Our MYC degradation screen identified novel protein kinases that regulate MYC protein stability; we will exploit these to cause MYC loss. Second, we have found that the ERK protein kinases are largely responsible for KRAS-dependent metabolic perturbations (autophagy, glycolysis, macropinocytosis, mitochondrial function). We suggest that targeting ERK, rather than the metabolic enzymes considered by the field, will be a more effective therapeutic strategy to target cancer metabolism. We will pursue an issue still largely neglected, the determination of the key ERK substrates that are critical for ERK-dependent KRAS-mutant PDAC growth. Third, as with other targeted therapies, anti-KRAS therapies will be limited by mechanisms of acquired resistance. While much of the field is focused on YAP1, it is also clear that YAP1-independent mechanisms will also play significant role in how cancers escape KRAS-dependency. We will apply experimental approaches not previously utilized to define these YAP1–independent mechanisms. These findings will be critical for development of anti-KRAS therapies that can achieve long-lasting clinical efficacy. Finally, our surprising finding that one KRAS mutant (G12R) cannot utilize a key RAS effector, PI3K, and drives metabolic activities distinct from the most prevalent KRAS mutations, provides our rationale to pursue outlier mutations in PDAC, to identify mutation-specific vulnerabilities as the basis for development of mutation-selective therapies. In summary, since adherence to long-held dogma has at times stifled progress, less mainstream directions must be taken if we are to finally achieve the breakthroughs needed for development of effective anti-RAS therapies.

项目概要/摘要 我的杰出研究者奖 (OIA) 研究计划将建立在我多年的研究主题之上 三十年的 RAS 研究，追求通常被 RAS 领域和 NCI RAS 忽视的方向 倡议，使“不可成药”的 RAS 可成药，我是最初提出这一方案的研究团队的成员。 自从这一发现以来，我的研究集中在人类癌症中激活的 RAS 癌基因上。 了解 RAS 蛋白的基本生物化学、信号传导和生物学，长期目标是 我的研究重点是胰腺 导管腺癌 (PDAC) 是一种尚待找到有效靶向治疗的癌症，占 95%。 KRAS 突变频率以及大量实验证据表明“纠正”KRAS 缺陷将 显着损害 PDAC 的生长，PDAC 可以说是最依赖 RAS 的癌症。 基于我们未发表的研究结果，“承担更大的风险，更具冒险精神”的研究。 3-4年前发起，现在刚刚取得成果，我已经确定了四个新的高风险/高回报 首先，尽管 RAS 和 MYC 之间存在明确的相互依赖性。 致癌基因驱动癌症生长，但我们并未广泛考虑将 MYC 作为抗 KRAS 策略。 MYC 降解筛选鉴定出调节 MYC 蛋白稳定性的新型蛋白激酶； 其次，我们发现 ERK 蛋白激酶是造成 MYC 损失的主要原因。 KRAS 依赖性代谢扰动（自噬、糖酵解、巨胞饮作用、线粒体功能）。 我们建议，针对 ERK，而不是该领域考虑的代谢酶，将是一种更有效的方法。 我们将研究一个仍被广泛忽视的问题，即针对癌症代谢的有效治疗策略。 确定对 ERK 依赖性 KRAS 突变 PDAC 生长至关重要的关键 ERK 底物。 第三，与其他靶向疗法一样，抗 KRAS 疗法将受到获得性机制的限制。 虽然该领域的大部分研究都集中在 YAP1 上，但很明显，独立于 YAP1 的机制也会产生耐药性。 在癌症如何摆脱 KRAS 依赖性方面也发挥着重要作用，我们将应用实验方法。 以前没有用来定义这些独立于 YAP1 的机制，这些发现对于 开发可以实现持久临床疗效的抗 KRAS 疗法最后，我们令人惊讶。 发现一种 KRAS 突变体 (G12R) 无法利用关键的 RAS 效应子 PI3K 并驱动代谢活动 与最常见的 KRAS 突变不同，为我们寻找 PDAC 异常突变提供了理由， 识别突变特异性脆弱性作为开发突变选择性疗法的基础。 总之，由于对长期坚持的教条的坚持有时会阻碍进步，因此必须采取非主流方向 如果我们要最终实现开发有效的抗 RAS 疗法所需的突破，就必须采取这一行动。