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。

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要致癌性Krasg12c（kg12c）突变是〜14％的非斑点非小细胞肺的发展。癌症（NSCLC）每年在美国占10,000人死亡，潜力，选择性和 KG12C癌蛋白的临床活性共价抑制剂代表了最令人兴奋的进步之一在有针对性的癌症疗法领域，但策略旨在规避自适应抗性和迫切需要提高对KG12C抑制剂的耐用性患者的结果。肿瘤细胞与肿瘤微环境（TME）之间串扰的作用迄今为止，尚未系统地检查获得的NSCLC中获得的KG12C抑制剂的耐药性尽管有证据表明，在超过50％的情况下，无法确定基因组抗性机制放射学进程的时间。此外，TME重塑和免疫逃生的关键介质对KG12C抑制剂疗法的反应仍然很差，并且针对不良TME的治疗策略为了预防，尚未建立延迟或克服KG12C抑制剂适应/获得的抗性。最后，STK11/LKB1和TP53中主要同时发生的基因组改变的影响，并塑造 KRAS突变NSCLC的免疫背景 - 在获得的KG12C抑制剂的非基因机制上不知道。根据我们的初步发现和以前的工作，我们假设：1。重塑肿瘤微环境和免疫逃生可以促进非肿瘤细胞自主适应/获得对KG12C抑制剂的抗性； 2。用TTI-101靶向STAT3信号可以阻止并可能克服通过对肿瘤细胞和/或TME的影响，非遗传学获得对KG12C抑制剂的抗性。在AIM 1中，我们将确定TME重塑和免疫逃逸对获得的KG12C抑制剂耐药性的贡献 NSCLC，使用KG12C NSCLC的免疫能力模型，该模型概括了其共透性复杂性。我们将进一步询问TME自适应重塑的主要介体的作用，最初关注STAT3，我们将使用来自转移性KG12C突变NSCLC患者的成对活检验证关键发现用Sotorasib作为护理标准的一部分进行处理。在AIM 2中，我们将评估抗肿瘤效率和TME- 用TTI-101抑制STAT3抑制作用与免疫中直接KG12C抑制剂结合 KG12C NSCLC的合格模型。临床意义：这项工作将产生对非基因的新见解依赖肿瘤-TME串扰的KG12C抑制剂的耐药机制，将促进开发新的治疗策略，以解决不良TME，以最大化长期临床受益于KG12C抑制剂。