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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的 KRAS 是人类癌症中最常见的突变基因之一。尽管发展取得了进步直接靶向突变 KRAS 的抑制剂以及 FDA 批准 KRASG12C 抑制剂 sotorasib 用于 KRASG12C- 突变型非小细胞肺癌（NSCLC），癌细胞的适应性和对KRAS抑制剂的耐药性几乎这是不可避免的，并且仍然是限制其临床益处的重大挑战。我们的初步数据确定蛋白质稳态重编程是介导肿瘤对 KRAS 抑制剂耐药的重要机制。致癌 KRAS 失活会迅速下调热休克反应 (HSR) 和 IRE1a 分支未折叠蛋白反应（UPR）。然而，在 KRASi 抗性中，只有 IRE1a 被选择性地重新激活。肿瘤。 IRE1a 的遗传或药理学抑制显着使 KRASG12C 突变肿瘤对 sotorasib，在临床前 NSCLC 和胰腺癌模型中产生完全且持久的反应。从机制上讲，我们发现致癌 KRAS-MAPK 信号通过直接促进 IRE1a 蛋白稳定性 ERK-IRE1a 相互作用。相比之下，KRASi 的多种耐药机制，包括重新激活的 ERK 和过度激活的 AKT，会在耐药肿瘤中重新激活 IRE1a。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，并进一步探索药物抑制蛋白质稳态重编程作为 KRAS 突变体抗肿瘤方法的效果癌症。我们假设 IRE1a 介导的蛋白质稳态重编程促进肿瘤对致癌 KRAS 抑制以及多种耐药途径与 IRE1a 汇聚以恢复蛋白质稳态并促进对 KRAS 抑制剂的治疗耐药性。该提案将确定以下分子机制：响应突变 KRAS 抑制的差异 IRE1a 调节（目标 1），定义蛋白质稳态机制 KRAS 突变癌症中 HSR 和 UPR 之间的串扰（目标 2），并评估 KRAS 突变癌症的治疗效果靶向蛋白质稳态重编程以克服 KRAS 突变癌症中的 KRASi 耐药性（目标 3）。实现这些目标将确立致癌信号传导的生物学意义和生化基础 KRAS 突变人类癌症中受调节的蛋白质稳态网络，导致开发出更有效和更有效的药物逆转 KRASi 耐药性并绕过靶向毒性的耐受性良好的治疗策略多种耐药信号通路。