Mechanisms of adaptation and resistance to emerging therapies for lung cancer

项目摘要/摘要 KRAS GTP酶的突变是癌症中最常见的功能获得改变之一。KRAS 在25%的肺癌患者中发现了突变，其中近一半涉及G12C替换。 肺癌是癌症相关死亡的主要原因，考虑到超过25万人 每年在美国被诊断出患有肺癌，开发出直接针对 KRAS癌蛋白是至关重要的。选择性靶向KRAS G12C的抑制剂的发现 一直是精确肿瘤学最令人兴奋的最新进展之一。我们之前已经证明了 抑制剂通过核苷酸阻止癌蛋白的重新激活，使其处于非活性(GDP结合)状态。 这种抑制需要癌细胞中突变的KRAS分解GTP。非活动 国家选择性KRAS G12C抑制剂(如Sotorasib和Adagrasib)的客观应答率为37%-43% (ORR)和6-8个月的中位无进展生存期(PFS)。索托拉西卜是 被美国食品和药物管理局(FDA)批准为KRAS G12C患者的二线治疗药物 突变的肺癌。尽管取得了这些初步的成功，但如果我们要显著地影响 KRAS突变癌症患者的存活率。目前的提案旨在找出导致 调节患者的药物适应性和耐药性，并确定改进的KRAS导向治疗方法 接近了。提案的第一部分建立在我们的临床前工作的基础上，表明同基因肺癌细胞 以非均匀的方式绕过G12C抑制。我们的初步数据表明，这是因为 有效G12Ci的构象特异性及其在某些药物治疗中新KRAS G12C的合成 细胞。在目标1中，我们将确定对抑制剂治疗的反应和适应的异质性。 靶向突变KRAS的活性或非活性构象。这些研究将在 在临床标本和患者衍生模型中并行，以确保稳健性和重复性。目标2 建立在我们最近研究使用索托拉西布或阿达格西布治疗的患者获得性耐药性的基础上。在这里我们 将专注于导致对新兴活性状态选择性药物产生耐药性的改变，最初依赖于 一旦这些药物于2022年底进入临床测试，就会在患者衍生的模型上，然后在临床样本上。在……里面 此外，对条形码种群的前瞻性研究将调查指导 选择引起抗性的改变。在目标3中，我们将研究改变或 在初步数据或目标1和2中确定的表型会导致抗性。KRAS的早期成功 G12C抑制剂启发了其他KRAS抑制剂的开发，这些药物正在进入临床试验和 承诺改善KRAS驱动的癌症患者的生存和生活质量。拟议的工作将 这对于最大限度地发挥这些期待已久的疗法的治疗潜力至关重要。

PROJECT SUMMARY/ABSTRACT Mutations in the KRAS GTPase are some of the most frequent gain-of-function alterations in cancer. KRAS mutations are found in 25% of patients with lung cancer and nearly half of these involve a G12C substitution. Lung cancer is the leading cause of cancer related mortality and, considering that more than 250,000 people are diagnosed each year with lung cancer in the US, developing therapeutic strategies that directly targeting KRAS oncoprotein is of paramount importance. The discovery of inhibitors that selectively target KRAS G12C has been one of the most exciting recent developments in precision oncology. We previously showed that the inhibitors trap the oncoprotein in an inactive (GDP-bound) state by blocking its reactivation by nucleotide exchange and that such inhibition requires the breakdown of GTP by mutant KRAS in cancer cells. Inactive state selective KRAS G12C inhibitors (e.g., sotorasib and adagrasib) have a 37-43% objective response rate (ORR) and a 6-8 month median progression free survival (PFS) in patients with lung cancer. Sotorasib was approved by the food and drug administration (FDA) as a second line treatment in patients with KRAS G12C- mutant lung cancer. Despite these early successes more work is needed if we are to dramatically affect the survival of patients with KRAS mutant cancer. The current proposal seeks to identify factors responsible for modulating drug adaptation and resistance in patients and to identify improved KRAS-directed therapeutic approaches. The first part of the proposal builds on our preclinical work showing that isogenic lung cancer cells bypass G12C inhibition in a non-uniform manner. Our preliminary data suggest this occurs because of the conformation-specific nature of available G12Ci and the synthesis of new KRAS G12C in some drug-treated cells. In Aim 1, we will determine the heterogeneity in response and adaptation to treatment with inhibitors targeting either the active or the inactive conformation of mutant KRAS. The studies will be performed in parallel in clinical specimens and in patient derived models to ensure robustness and reproducibility. Aim 2 builds on our recent effort to study acquired resistance in patients treated with sotorasib or adagrasib. Here we will focus on alterations that cause resistance to emerging active state selective drugs, relying initially on patient-derived models and then on clinical specimens, once these drugs enter clinical testing in late 2022. In addition, prospective studies with barcoded populations will investigate the clonal interactions that guide the selection of resistance-causing alterations. In Aim 3 we will study the mechanisms by which the alterations or phenotypes identified in the preliminary data or in Aims 1 and 2 lead to resistance. The early success of KRAS G12C inhibitors has inspired the development of additional KRAS inhibitors that are entering clinical trials and promise to improve the survival and quality of life of patients with KRAS driven cancer. The proposed work will be of vital importance in maximizing the therapeutic potential of these long-awaited therapies.