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

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)突变支持~14%的非鳞状非小细胞肺的发生 癌症(NSCLC),在美国每年造成约10,000人死亡。有效、选择性和 临床上具有活性的KG12C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,然而,规避适应性耐药和 提高个体对KG12C抑制剂反应的持久性是转变临床急需的 患者的结果。肿瘤细胞与肿瘤微环境(TME)之间的串扰在肿瘤生长中的作用 获得性KG12C抑制剂耐药性在非小细胞肺癌中的发展到目前为止还没有得到系统的研究。 尽管有证据表明,在超过50%的病例中,在 放射进展时间。此外,TME重塑和免疫逃逸的关键介质在 对KG12C抑制剂治疗的反应仍不明确,针对不良TME的治疗策略 为了预防、推迟或克服KG12C抑制剂的适应/获得性耐药,尚未建立。 最后,STK11/LKB1和TP53的主要共生基因组改变的影响以及塑造 KRAS突变型NSCLC的免疫环境--获得性KG12C抑制剂耐药的非遗传机制 是未知的。根据我们的初步发现和以前的工作,我们假设:1.椎体重塑 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抑制剂的抗性;2.TTI-101靶向STAT3信号转导可以阻止并可能克服 KG12C抑制剂通过对肿瘤细胞和/或TME的影响而产生的非遗传性获得性耐药性。在目标1中,我们 将确定TME重塑和免疫逃逸在获得性KG12C抑制剂抵抗中的作用 NSCLC,使用KG12C NSCLC的免疫活性模型,概括了其共突变的复杂性。我们会 进一步询问TME适应性重塑的主要调节因子的作用,最初的焦点是STAT3和WE 将使用转移性KG12C突变非小细胞肺癌患者的配对活检来验证关键发现 作为标准护理的一部分,使用sotorasib治疗。在目标2中,我们将评估其抗肿瘤效果和TME-2。 TTI-101联合直接KG12C抑制剂对STAT3抑制的免疫调节作用 KG12C NSCLC的称职机型。临床意义:这项工作将对非遗传性疾病产生新的见解 KG12C抑制剂获得性耐药性的机制依赖于肿瘤-TME串扰,并将促进 开发新的治疗策略来处理不良的TME,以最大化长期临床疗效 受益于KG12C抑制剂。

项目成果

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Ferdinandos Skoulidis其他文献

Ferdinandos Skoulidis的其他文献

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{{ truncateString('Ferdinandos Skoulidis', 18)}}的其他基金

Dissecting and targeting mechanisms of genomic instability-triggered immune evasion in RBM10-deficient non-small cell lung cancer
RBM10 缺陷型非小细胞肺癌基因组不稳定性触发免疫逃逸的剖析和靶向机制
  • 批准号:
    10658049
  • 财政年份:
    2023
  • 资助金额:
    $ 37.06万
  • 项目类别:
Understanding and harnessing immune-modulatory effects of covalent KRASG12C inhibitors in KRASG12C-mutant non-small cell lung cancer
了解和利用共价 KRASG12C 抑制剂对 KRASG12C 突变非小细胞肺癌的免疫调节作用
  • 批准号:
    10478950
  • 财政年份:
    2021
  • 资助金额:
    $ 37.06万
  • 项目类别:
Understanding and harnessing immune-modulatory effects of covalent KRASG12C inhibitors in KRASG12C-mutant non-small cell lung cancer
了解和利用共价 KRASG12C 抑制剂对 KRASG12C 突变非小细胞肺癌的免疫调节作用
  • 批准号:
    10675537
  • 财政年份:
    2021
  • 资助金额:
    $ 37.06万
  • 项目类别:
Understanding and harnessing immune-modulatory effects of covalent KRASG12C inhibitors in KRASG12C-mutant non-small cell lung cancer
了解和利用共价 KRASG12C 抑制剂对 KRASG12C 突变非小细胞肺癌的免疫调节作用
  • 批准号:
    10276919
  • 财政年份:
    2021
  • 资助金额:
    $ 37.06万
  • 项目类别:

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