Proteostasis Reprogramming in Mutant KRAS-Driven Cancers

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KRAS的抑制剂和FDA批准KRASG12C抑制剂sotorasib用于KRASG12C- 突变型非小细胞肺癌(NSCLC)的癌细胞适应性和对KRAS抑制剂的耐药性几乎 这是不可避免的，而且仍然是限制其临床益处的主要挑战。我们的初步数据证实 蛋白稳定重编程是介导肿瘤对KRAS抑制剂耐药的重要机制。 致癌KRAS的失活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的遗传或药物抑制显著增强KRASG12C突变肿瘤对 Sotorasib，在临床前NSCLC和胰腺癌模型中导致完全和持久的反应。 从机制上讲，我们发现致癌的KRAS-MAPK信号通过直接 ERK-IRE1a相互作用。相比之下，对Krasi的多种抵抗机制，包括重新激活的ERK和 在耐药肿瘤中，过度激活的AKT会聚在一起重新激活IRE1a。这些发现提供了一个框架，以 寻求对KRAS突变癌症中蛋白质平衡重编程的生物学洞察，并进一步探索 药物抑制蛋白抑制剂重编程对KRAS突变体的抗肿瘤作用 癌症。我们假设IRE1a介导的蛋白平衡重编程促进肿瘤对 致癌的KRAS抑制和多条耐药途径与IRE1a汇聚以恢复蛋白平衡 并促进对KRAS抑制剂的治疗耐药性。这一提议将决定分子机制 对突变的KRAS抑制反应的不同IRE1a调节(目标1)，定义蛋白平衡机制 KRAS突变癌中HSR和UPR之间的串扰(AIM 2)，并评价其治疗效果 靶向蛋白平衡重编程以克服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平衡网络，导致开发更有效和 耐受性良好的逆转Krasi耐药性并绕过靶向毒性的治疗策略 多条抗性信号通路。

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.