Dissecting and targeting tumor-TME crosstalk to forestall acquired KRASG12C inhibitor resistance in NSCLC.

项目总结/摘要 致癌性KRASG 12 C（KG 12 C）突变支持约14%的非鳞状非小细胞肺 美国每年约有10，000人死于非小细胞肺癌（NSCLC）。强效、选择性和抗肿瘤药物的开发 具有临床活性的KG 12 C癌蛋白共价抑制剂代表了最令人兴奋的最新进展之一 在靶向癌症治疗领域，避免适应性耐药性发展的策略， 迫切需要改善对KG 12 C抑制剂的个体应答的持久性，以改变临床 患者的结果。肿瘤细胞和肿瘤微环境（TME）之间的串扰在肿瘤细胞凋亡中的作用 迄今为止尚未系统地研究NSCLC中获得性KG 12 C抑制剂耐药性的发展， 尽管有证据表明，在超过50%的情况下，在基因组水平上不能鉴定出基因组抗性机制， 放射学进展时间。此外，TME重塑和免疫逃逸的关键介质， 对KG 12 C抑制剂治疗的反应仍然不明确，针对不良TME的治疗策略 以预防、延迟或克服KG 12 C抑制剂适应/获得性抗性的方法尚未建立。 最后，研究了STK 11/LKB 1和TP 53中主要共同发生的基因组改变的影响，这些改变塑造了 KRAS突变非小细胞肺癌免疫结构--获得性KG 12 C抑制剂耐药的非遗传机制 是未知的。根据我们的初步研究结果和以前的工作，我们假设：1。重塑 肿瘤微环境和免疫逃逸可以促进非肿瘤细胞的自主适应/获得 对KG 12 C抑制剂的抗性; 2.用TTI-101靶向STAT 3信令可以阻止并且可能克服 通过对肿瘤细胞和/或TME的作用对KG 12 C抑制剂产生非遗传获得性耐药性。目标1： 将确定TME重塑和免疫逃逸对获得性KG 12 C抑制剂耐药性的贡献， NSCLC，使用重现其共突变复杂性的KG 12 C NSCLC免疫活性模型。我们将 进一步探讨TME适应性重塑的主要介质的作用，最初关注STAT 3， 将使用来自转移性KG 12 C突变型NSCLC患者的配对活检来验证关键发现， 作为标准治疗的一部分使用sotorasib治疗。在目标2中，我们将评估抗肿瘤功效和TME-1。 TTI-101与直接KG 12 C抑制剂组合在免疫系统中的STAT 3抑制的改变作用 KG 12 C NSCLC的合格模型。临床意义：这项工作将产生新的见解，非遗传 对依赖于肿瘤-TME串扰的KG 12 C抑制剂的获得性耐药机制， 开发新的治疗策略，解决不良TME，以最大限度地提高长期临床疗效 从KG 12 C抑制剂中获益。

PROJECT SUMMARY/ABSTRACT Oncogenic KRASG12C (KG12C) mutations underpin the development of ~14% of non-squamous non-small cell lung cancer (NSCLC) and account for ~10,000 deaths annually in the U.S. The development of potent, selective and clinically active covalent inhibitors of the KG12C oncoprotein represents one of the most exciting recent advances in the field of targeted cancer therapy, yet strategies to circumvent the development of adaptive resistance and improve the durability of individual responses to KG12C inhibitors are urgently needed in order to transform clinical outcomes for patients. The role of crosstalk between tumor cells and the tumor microenvironment (TME) in the development of acquired KG12C inhibitor resistance in NSCLC has not been systematically examined to date, despite evidence that in more than 50% of cases no genomic resistance mechanisms can be identified at the time of radiological progression. Furthermore, key mediators of TME remodeling and immune escape in response to KG12C inhibitor therapy remain poorly defined and therapeutic strategies that target the adverse TME in order to prevent, delay or overcome KG12C inhibitor adaptation/acquired resistance have not been established. Finally, the impact of major co-occurring genomic alterations in STK11/LKB1 and TP53 and that shape the immune contexture of KRAS-mutant NSCLC– on non-genetic mechanisms of acquired KG12C inhibitor resistance is not known. Based on our preliminary findings and previous work we hypothesize that: 1. Remodeling of the tumor microenvironment and immune escape can promote non-tumor cell autonomous adaptation/acquired resistance to KG12C inhibitors; 2. Targeting STAT3 signaling with TTI-101 can forestall and possibly overcome non-genetic acquired resistance to KG12C inhibitors through effects on tumor cells and/or the TME. In Aim 1, we will determine the contribution of TME remodeling and immune escape to acquired KG12C inhibitor resistance in NSCLC, using immune competent models of KG12C NSCLC that recapitulate its co-mutational complexity. We will further interrogate the role of master mediators of TME adaptive remodeling with initial focus on STAT3 and we will validate key findings using paired biopsies from patients with metastatic KG12C-mutant NSCLC that were treated with sotorasib as part of standard of care. In Aim 2, we will evaluate the anti-tumor efficacy and TME- modifying effects of STAT3 inhibition with TTI-101 in combination with direct KG12C inhibitors in immune- competent models of KG12C NSCLC. Clinical significance: This work will yield fresh insights into non-genetic mechanisms of acquired resistance to KG12C inhibitors that rely on tumor-TME crosstalk and will facilitate the development of novel therapeutic strategies that tackle the adverse TME in order to maximize long-term clinical benefit from KG12C inhibitors.