Proteostasis Reprogramming in Mutant KRAS-Driven Cancers

突变 KRAS 驱动的癌症中的蛋白质稳态重编程

• 批准号: 10587281
• 负责人: Xi Chen
• 金额: $ 51.54万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587281
• 关键词: Ablation; Biochemical; Biological; Bypass; Cell Survival; Cells; Chronic; Clinical; Colorectal Cancer; Combined Modality Therapy; Data; Development; Dose Limiting; Genes; Genetic; Genetically Engineered Mouse; HSF1; Heat-Shock Response; Human; Individual; KRAS oncogenesis; KRAS2 gene; KRASG12D; Laboratory Study; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Membrane; Molecular; Monitor; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenic; PIK3CG gene; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phase II Clinical Trials; Phosphorylation; Phosphorylation Site; Post-Translational Protein Processing; Pre-Clinical Model; Protein Secretion; Proteins; Proteome; Proto-Oncogene Proteins c-akt; Quality Control; Regulation; Relapse; Research; Resistance; Ribonucleases; Signal Pathway; Signal Transduction; Specificity; Stress; Therapeutic; Toxic effect; Treatment Efficacy; Ubiquitination; cancer cell; clinically relevant; improved; in vivo; inhibitor; insight; mutant; novel therapeutic intervention; pancreatic cancer model; patient derived xenograft model; patient response; pharmacologic; pre-clinical; preclinical trial; prevent; protein aggregation; proteostasis; proteotoxicity; refractory cancer; resistance mechanism; response; therapy resistant; tumor; tumor growth; tumorigenesis

ABSTRACT KRAS is one of the most frequently mutated genes in human cancers. Despite advances in the development of inhibitors that directly target mutant KRAS and the FDA approval of KRASG12C inhibitor sotorasib for KRASG12C- mutant non-small cell lung cancer (NSCLC), cancer cell adaptation and resistance to KRAS inhibitors are almost inevitable and remains a major challenge that limits their clinical benefits. Our preliminary data establish proteostasis reprogramming as an essential mechanism that mediates tumor resistance to KRAS inhibitor. Inactivation of oncogenic KRAS rapidly downregulates both the heat shock response (HSR) and IRE1a branch of the unfolded protein response (UPR). However, only IRE1a is selectively reactivated in KRASi-resistant tumors. Genetic or pharmacologic suppression of IRE1a substantially sensitizes KRASG12C-mutant tumors to sotorasib, leading to complete and durable responses in preclinical NSCLC and pancreatic cancer models. Mechanistically, we found that oncogenic KRAS-MAPK signaling promotes IRE1a protein stability through direct ERK-IRE1a interaction. In contrast, multiple mechanisms of resistance to KRASi, including reactivated ERK and hyperactivated AKT, converge to re-activate IRE1a in resistant tumors. These findings provide a framework to seek biological insight into the proteostasis reprogramming in KRAS-mutant cancers, and to further explore the effects of pharmacological inhibition of proteostasis reprogramming as an anti-tumor approach for KRAS-mutant cancers. We hypothesize that IRE1a-mediated proteostasis reprogramming facilitates tumor resistance to oncogenic KRAS inhibition and that multiple resistance pathways converge with IRE1a to restore proteostasis and promote therapy resistance to KRAS inhibitors. This proposal will determine the molecular mechanisms of differential IRE1a regulation in response to mutant KRAS inhibition (Aim 1), define proteostasis machinery crosstalk between HSR and UPR in KRAS-mutant cancers (Aim 2), and evaluate the therapeutic efficacy of targeting proteostasis reprogramming to overcome KRASi resistance in KRAS-mutant cancers (Aim 3). Accomplishing these aims will establish the biological significance and biochemical basis of oncogenic signaling regulated proteostasis network in KRAS-mutant human cancers, leading to development of more effective and well-tolerated therapeutic strategy to reverse KRASi resistance and bypass the on-target toxicity of targeting multiple resistance signaling pathways.

摘要 KRAS是人类癌症中最常见的突变基因之一。尽管在发展方面取得了进展， 直接靶向突变型KRAS的抑制剂和FDA批准KRASG 12 C抑制剂sotorasib用于KRASG 12 C- 突变型非小细胞肺癌（NSCLC），癌细胞适应性和对KRAS抑制剂的耐药性几乎是 这是不可避免的，并且仍然是限制其临床益处的主要挑战。我们的初步数据表明 蛋白质稳态重编程是介导肿瘤对KRAS抑制剂耐药性的重要机制。 致癌KRAS的失活快速下调热休克反应（HSR）和IRE 1 a分支 未折叠蛋白反应（UPR）然而，只有IRE 1a在KRASi抗性细胞中被选择性地重新激活， 肿瘤的IRE 1a的遗传或药理学抑制实质上使KRASG 12 C突变型肿瘤对以下物质敏感： sotorasib，导致临床前NSCLC和胰腺癌模型的完全和持久的反应。 从机制上讲，我们发现致癌KRAS-MAPK信号通过直接作用促进IRE 1a蛋白的稳定性， ERK-IRE 1a相互作用。相反，对KRASi的多种耐药机制，包括重新激活的ERK和 过度活化AKT，在耐药肿瘤中会聚以再活化IRE 1a。这些发现提供了一个框架， 寻求对KRAS突变癌症中蛋白质稳态重编程的生物学见解，并进一步探索 药理学抑制蛋白质稳态重编程作为KRAS突变体的抗肿瘤方法的作用 癌的我们假设IRE 1a介导的蛋白质抑制重编程促进了肿瘤对 致癌KRAS抑制和多种耐药途径与IRE 1a汇合以恢复蛋白质稳态 并促进对KRAS抑制剂的治疗抗性。这一建议将确定的分子机制， 不同的IRE 1a调节响应突变KRAS抑制（目的1），定义蛋白质稳定机制 KRAS突变型癌症中HSR和UPR之间的串扰（目的2），并评估 靶向蛋白质抑制重编程以克服KRAS突变型癌症中的KRASi抗性（目标3）。 这些目标的实现将有助于建立致癌信号转导的生物学意义和生化基础 在KRAS突变的人类癌症中调节蛋白质稳态网络，从而开发出更有效， 耐受性良好的治疗策略，以逆转KRASi耐药性并绕过靶向的靶向毒性 多种抗性信号通路。