Department of Oncology, University of Torino, Candiolo, Italy.
Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
Gastric Cancer. 2024 May;27(3):473-483. doi: 10.1007/s10120-024-01468-8. Epub 2024 Jan 23.
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide, with a poor prognosis for patients with advanced disease. Since the oncogenic role of KRAS mutants has been poorly investigated in GC, this study aims to biochemically and biologically characterize different KRAS-mutated models and unravel differences among KRAS mutants in response to therapy.
Taking advantage of a proprietary, molecularly annotated platform of more than 200 GC PDXs (patient-derived xenografts), we identified KRAS-mutated PDXs, from which primary cell lines were established. The different mutants were challenged with KRAS downstream inhibitors in in vitro and in vivo experiments.
Cells expressing the rare KRAS A146T mutant showed lower RAS-GTP levels compared to those bearing the canonical G12/13D mutations. Nevertheless, all the KRAS-mutated cells displayed KRAS addiction. Surprisingly, even if the GEF SOS1 is considered critical for the activation of KRAS A146T mutants, its abrogation did not significantly affect cell viability. From the pharmacologic point of view, Trametinib monotherapy was more effective in A146T than in G12D-mutated models, suggesting a vulnerability to MEK inhibition. However, in the presence of mutations in the PI3K pathway, more frequently co-occurrent in A146T models, the association of Trametinib and the AKT inhibitor MK-2206 was required to optimize the response.
A deeper genomic and biological characterization of KRAS mutants might sustain the development of more efficient and long-lasting therapeutic options for patients harbouring KRAS-driven GC.
胃癌（GC）是全球癌症相关死亡的第三大主要原因，晚期患者预后较差。由于 KRAS 突变体的致癌作用在 GC 中研究甚少，本研究旨在对不同 KRAS 突变模型进行生化和生物学特征分析，并揭示 KRAS 突变体在治疗反应方面的差异。
利用我们拥有的 200 多个 GC PDX（患者来源的异种移植物）的专有、分子注释平台，我们鉴定了 KRAS 突变的 PDX，并从中建立了原代细胞系。在体外和体内实验中，用 KRAS 下游抑制剂对不同的突变体进行了挑战。
表达罕见 KRAS A146T 突变的细胞与携带典型 G12/13D 突变的细胞相比，RAS-GTP 水平较低。然而，所有 KRAS 突变细胞都表现出 KRAS 依赖性。令人惊讶的是，即使 GEF SOS1 被认为对 KRAS A146T 突变体的激活至关重要，但它的缺失并不显著影响细胞活力。从药理学角度来看，Trametinib 单药治疗在 A146T 模型中比在 G12D 突变模型中更有效，表明对 MEK 抑制的敏感性。然而，在 PI3K 通路存在突变的情况下，A146T 模型中更常同时存在这些突变，需要联合使用 Trametinib 和 AKT 抑制剂 MK-2206 才能优化反应。
对 KRAS 突变体进行更深入的基因组和生物学特征分析，可以为携带 KRAS 驱动的 GC 的患者提供更有效和持久的治疗选择。
