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

剖析和靶向肿瘤-TME 串扰，以预防 NSCLC 中获得性 KRASG12C 抑制剂耐药性。

• 批准号: 10634271
• 负责人: Ferdinandos Skoulidis
• 金额: $ 37.06万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-17 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634271
• 关键词: Acute; Animal Model; Architecture; Autopsy; Bioinformatics; Biology; Biometry; Biopsy; Bypass; Cancer Center; Cancer Patient; Cells; Cessation of life; Clinical; DNA Sequence Alteration; Data; Dependence; Development; Extinction; Failure; Genetic Engineering; Genomics; Immune; Immunobiology; Immunocompetent; Immunogenomics; Immunology procedure; In Vitro; KRAS2 gene; MAP Kinase Gene; Malignant Neoplasms; Mediator; Medical Oncology; Modeling; Molecular; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenic; Oncoproteins; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Phosphorylation; Pre-Clinical Model; Property; Publications; Radiology Specialty; Refractory; Reporting; Resistance; Resolution; Role; STAT3 gene; STK11 gene; Sampling; Shapes; Signal Transduction; Specimen; TP53 gene; Therapeutic; Time; Tumor Escape; Tumor Suppressor Genes; Tyrosine; Work; biobank; clinical development; clinical efficacy; clinically significant; improved; individual response; inhibitor; inhibitor therapy; insight; molecular pathology; mouse model; mutant; neoplastic cell; non-genetic; novel; novel therapeutic intervention; objective response rate; prevent; resistance mechanism; response; single-cell RNA sequencing; small molecule; standard of care; synergism; targeted cancer therapy; therapeutic target; tumor; tumor microenvironment

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.

项目概要/摘要 致癌 KRASG12C (KG12C) 突变支撑约 14% 的非鳞状非小细胞肺的发育 癌症 (NSCLC) 每年导致美国约 10,000 人死亡。 KG12C 癌蛋白的临床活性共价抑制剂代表了最新最令人兴奋的进展之一 在靶向癌症治疗领域，还存在规避适应性耐药性和 为了改变临床现状，迫切需要提高个体对 KG12C 抑制剂反应的持久性 患者的结果。肿瘤细胞与肿瘤微环境（TME）之间的串扰在 迄今为止，尚未系统地检查 NSCLC 中获得性 KG12C 抑制剂耐药性的发展， 尽管有证据表明，在超过 50% 的病例中，无法在基因组中识别出耐药机制 放射学进展的时间。此外，TME 重塑和免疫逃逸的关键介质 对 KG12C 抑制剂治疗的反应仍不明确，针对不良 TME 的治疗策略 尚未确定如何预防、延迟或克服 KG12C 抑制剂适应/获得性耐药性。 最后，STK11/LKB1 和 TP53 中主要同时发生的基因组改变的影响以及塑造 KRAS 突变 NSCLC 的免疫环境——关于获得性 KG12C 抑制剂耐药性的非遗传机制 尚不清楚。根据我们的初步发现和之前的工作，我们假设： 1. 重塑 肿瘤微环境和免疫逃逸可促进非肿瘤细胞自主适应/获得性 对 KG12C 抑制剂的耐药性； 2. 使用 TTI-101 靶向 STAT3 信号传导可以预防并可能克服 通过对肿瘤细胞和/或 TME 的影响，获得对 KG12C 抑制剂的非遗传性耐药性。在目标 1 中，我们 将确定 TME 重塑和免疫逃逸对获得性 KG12C 抑制剂耐药性的贡献 NSCLC，使用 KG12C NSCLC 的免疫活性模型来概括其共突变复杂性。我们将 进一步询问 TME 适应性重塑的主要介导者的作用，最初关注 STAT3，我们 将使用来自转移性 KG12C 突变 NSCLC 患者的配对活检来验证关键发现，这些患者是 作为标准护理的一部分，使用 sotorasib 进行治疗。在目标2中，我们将评估抗肿瘤功效和TME- TTI-101 与直接 KG12C 抑制剂联合使用可改变免疫组化中 STAT3 抑制的效果 KG12C NSCLC 的感受态模型。临床意义：这项工作将为非遗传性疾病带来新的见解 对 KG12C 抑制剂的获得性耐药机制依赖于肿瘤-TME 串扰，并将促进 开发新的治疗策略来解决不良 TME，以最大限度地提高长期临床效果 受益于 KG12C 抑制剂。