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Targeting undruggable RAS for cancer treatment

靶向不可成药的 RAS 进行癌症治疗

基本信息

批准号：
10669038
负责人：
CHANNING J. DER
金额：
$ 90.25万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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

项目摘要

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 Based on our unpublished findings from studies initiated 3-4 years ago and just now coming into fruition, I have identified four new high risk / high reward research directions.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

项目总结/摘要我的杰出研究者奖（OIA）的研究计划将建立在我的多个主题，三十年的RAS研究，追求RAS领域和NCI RAS通常忽略的方向倡议，使“不可药用”的RAS可药用。我是研究小组的一员，鉴定人类癌症中激活的RAS癌基因。自从那次发现之后我的研究集中在了解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），一种仍有待发现有效靶向治疗的癌症。 KRAS突变频率和大量的实验证据表明，“纠正”KRAS缺陷将由于RAS显著损害PDAC生长，PDAC可以说是最依赖RAS的癌症。OIA支持研究“冒更大的风险，更冒险”。根据我们未发表的研究结果，我在3-4年前开始，现在刚刚开始实现，我已经确定了四个新的高风险/高回报研究方向。首先，尽管RAS和MYC之间存在着良好的相互依赖关系，在驱动癌症生长的致癌基因中，靶向MYC作为抗KRAS策略并未被广泛考虑。我们 MYC降解筛选确定了调节MYC蛋白稳定性的新型蛋白激酶;我们将利用这些都是造成MYC损失的原因。其次，我们发现ERK蛋白激酶主要负责 KRAS依赖性代谢紊乱（自噬、糖酵解、巨胞饮、线粒体功能）。我们认为，靶向ERK，而不是该领域考虑的代谢酶，将是一个更好的选择。靶向癌症代谢的有效治疗策略。我们将继续探讨一个在很大程度上仍被忽视的问题，确定对ERK依赖性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治疗将受到获得性免疫缺陷机制的限制。阻力虽然该领域的大部分都集中在YAP 1上，但很明显，独立于YAP 1的机制将在癌症如何摆脱KRAS依赖性方面也起着重要作用。我们将采用实验方法以前没有用于定义这些YAP 1独立的机制。这些发现将是至关重要的开发抗KRAS疗法，可实现持久的临床疗效。最后，我们的惊喜发现一种KRAS突变体（G12 R）不能利用关键的RAS效应子PI 3 K，并驱动代谢活动与最普遍的KRAS突变不同，为我们在PDAC中寻找离群突变提供了理论基础，确定突变特异性的脆弱性，作为发展突变选择性疗法的基础。在总而言之，由于坚持长期以来的教条有时会扼杀进步，因此非主流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，就必须采取这些措施。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Characterization of TR-107, a novel chemical activator of the human mitochondrial protease ClpP.

DOI：
10.1002/prp2.993
发表时间：
2022-08
期刊：
PHARMACOLOGY RESEARCH & PERSPECTIVES
影响因子：
2.6
作者：
Fennell, Emily M. J.;Aponte-Collazo, Lucas J.;Wynn, Joshua D.;Drizyte-Miller, Kristina;Leung, Elisa;Greer, Yoshimi Endo;Graves, Paul R.;Iwanowicz, Andrew A.;Ashamalla, Hani;Holmuhamedov, Ekhson;Lang, Henk;Karanewsky, Donald S.;Der, Channing J.;Houry, Walid A.;Lipkowitz, Stanley;Iwanowicz, Edwin J.;Graves, Lee M.
通讯作者：
Graves, Lee M.

Detection of phenotype-specific therapeutic vulnerabilities in breast cells using a CRISPR loss-of-function screen.

DOI：
10.1002/1878-0261.12951
发表时间：
2021-08
期刊：
Molecular oncology
影响因子：
6.6
作者：
Barkovskaya A;Goodwin CM;Seip K;Hilmarsdottir B;Pettersen S;Stalnecker C;Engebraaten O;Briem E;Der CJ;Moestue SA;Gudjonsson T;Maelandsmo GM;Prasmickaite L
通讯作者：
Prasmickaite L

Validation of Isoform- and Mutation-Specific RAS Antibodies.

同种型和突变特异性 RAS 抗体的验证。