Targeting undruggable RAS for cancer treatment

项目摘要/摘要 我的杰出调查员奖(OIA)研究计划将建立在我的 三十年的RAS研究，追求的方向通常被RAS领域和NCI RAS忽视 倡议，使“不能下药”的RAS可下药。我是研究团队的一员，这个团队做出了最初的 人类癌症中活化的RAS癌基因的鉴定。自那次发现以来，我的研究主要集中在 了解RAS蛋白的基本生物化学、信号和生物学，长期目标是 利用这些信息开发抗RAS癌症疗法。我的研究重点是胰腺 导管腺癌(PDAC)，一种有效的靶向治疗仍未找到的癌症。高达95% KRAS突变频率和大量实验证据表明“纠正”KRAS缺陷将 PDAC显著阻碍了PDAC的生长，PDAC可以说是RAS成瘾最严重的癌症。内审办支持 研究表明，“承担(S)更大的风险，[是]更具冒险精神”。基于我们未发表的研究结果 3-4年前开始的，刚刚开花结果，我已经确定了四个新的高风险/高回报 研究方向。第一，尽管RAS和MYC之间建立了良好的相互依存关系 在推动癌症生长的癌基因中，将MYC作为抗KRAS的策略并未被广泛考虑。我们的 MYC降解筛查发现了调节MYC蛋白稳定性的新蛋白激酶；我们将开发 这些都会造成MYC的损失。其次，我们发现ERK蛋白激酶在很大程度上是 依赖KRAS的代谢紊乱(自噬、糖酵解、巨噬细胞吞噬、线粒体功能)。 我们建议，靶向ERK，而不是该领域所考虑的代谢酶，将是一个更 针对癌症新陈代谢的有效治疗策略。我们将探讨一个在很大程度上仍被忽视的问题，即 确定对依赖ERK的KRAS突变体PDAC生长至关重要的关键ERK底物。 第三，与其他靶向治疗一样，抗KRAS治疗将受到获得性机制的限制 抵抗。虽然大部分领域都集中在YAP1上，但也很明显，与YAP1无关的机制将 在癌症如何逃脱对KRAS的依赖方面也发挥了重要作用。我们将应用实验方法 以前没有用来定义这些与YAP1无关的机制。这些发现将对 开发能达到长期临床疗效的抗KRAS疗法。最后，我们的惊喜 发现一个KRAS突变体(G12R)不能利用关键的RAS效应器PI3K，并驱动代谢活动 与最普遍的KRAS突变不同，这提供了我们在PDAC中寻找异常突变的理由， 确定突变特定的脆弱性，作为开发突变选择性治疗的基础。在……里面 总而言之，由于坚持长期坚持的教条有时会扼杀进步，不那么主流的方向必须 如果我们要最终实现开发有效的抗RAS疗法所需的突破，就必须采取行动。

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 Based on our unpublished findings from studies initiated 3-4 years ago and just now coming into fruition, I have identified four new high risk / high reward research directions.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.