KRAS 激活突变被认为是最常见的致癌驱动因素，与多种癌症（包括非小细胞肺癌 (NSCLC) 和结直肠癌）的放射抗性相关。尽管直到最近 KRAS 还被认为是不可成药的，但几种 KRAS 抑制剂最近已进入临床开发阶段。其中，MRTX849（Mirati Therapeutics）在治疗选定的 KRASG12C 突变非小细胞肺癌和结直肠癌患者方面显示出令人鼓舞的临床结果。在这项工作中，我们探索了 MRTX1257（一种类似于 MRTX849 的 KRASG12C 抑制剂）对 KRASG12C/突变细胞系和肿瘤放射增敏的能力。使用了与 MRTX1257 相关的体外和体内放射治疗 (RT) 模型，不同的 RAS 突变谱。我们在体外评估了 MRTX1257 在 CT26 KRASG12C / 、CT26 WT、LL2 WT 和 LL2 NRAS KO (LL2 NRAS-/-) 细胞系中的放射增敏作用。在体内，我们使用 BALB/c 小鼠和 T 细胞缺陷型无胸腺 nu/nu 小鼠的皮下 CT26 KRASG12C / 肿瘤同基因模型来评估 MRTX1257 的放射增敏作用及其免疫学特征。 MRTX1257 能够对 CT26 进行放射增敏。 KRASG12C/细胞在体外以时间和剂量依赖性方式进行。此外，在携带 CT26 KRASG12C/皮下肿瘤的 BALB/c 小鼠中，RT 与 MRTX1257 联合治疗可观察到 20% 的治愈率。然而，在无胸腺裸鼠中采用类似的治疗没有观察到持久的反应。 RT和MRTX1257后CT26 KRASG12C/肿瘤的免疫微环境分析显示，各种细胞亚型的比例增加，包括常规CD4  T细胞、2型树突状细胞(cDC2)和炎性单核细胞。此外，PD-L1 的表达在肿瘤和骨髓细胞中均显着下调，从而说明联合治疗后肿瘤微环境向促炎和抗肿瘤表型极化。这项工作是第一个证明MRTX1257（一种与口服给药相容的强效 KRASG12C 抑制剂）在 CT26 KRASG12C 突变细胞系和肿瘤中的体外和体内放射增敏作用。这是在 KRASG12C 突变肿瘤中使用 KRAS 抑制剂和 RT 的新组合策略的第一步，这种突变肿瘤在 NSCLC 中最为常见，14% 的患者具有这种突变特征。© 2023。作者。

KRAS activating mutations are considered the most frequent oncogenic drivers and are correlated with radio-resistance in multiple cancers including non-small cell lung cancer (NSCLC) and colorectal cancer. Although KRAS was considered undruggable until recently, several KRAS inhibitors have recently reached clinical development. Among them, MRTX849 (Mirati Therapeutics) showed encouraging clinical outcomes for the treatment of selected patients with KRASG12C mutated NSCLC and colorectal cancers. In this work, we explore the ability of MRTX1257, a KRASG12C inhibitor analogous to MRTX849, to radio-sensitize KRASG12C+/+ mutated cell lines and tumors.Both in vitro and in vivo models of radiotherapy (RT) in association with MRTX1257 were used, with different RAS mutational profiles. We assessed in vitro the radio-sensitizing effect of MRTX1257 in CT26 KRASG12C+/+, CT26 WT, LL2 WT and LL2 NRAS KO (LL2 NRAS-/-) cell lines. In vivo, we used syngeneic models of subcutaneous CT26 KRASG12C+/+ tumors in BALB/c mice and T cell deficient athymic nu/nu mice to assess both the radio-sensitizing effect of MRTX1257 and its immunological features.MRTX1257 was able to radio-sensitize CT26 KRASG12C+/+ cells in vitro in a time and dose dependent manner. Moreover, RT in association with MRTX1257 in BALB/c mice bearing CT26 KRASG12C+/+ subcutaneous tumors resulted in an observable cure rate of 20%. However, no durable response was observed with similar treatment in athymic nude mice. The analysis of the immune microenvironment of CT26 KRASG12C+/+ tumors following RT and MRTX1257 showed an increase in the proportion of various cell subtypes including conventional CD4 + T cells, dendritic cells type 2 (cDC2) and inflammatory monocytes. Furthermore, the expression of PD-L1 was dramatically down-regulated within both tumor and myeloid cells, thus illustrating the polarization of the tumor microenvironment towards a pro-inflammatory and anti-tumor phenotype following the combined treatment.This work is the first to demonstrate in vitro as in vivo the radio-sensitizing effect of MRTX1257, a potent KRASG12C inhibitor compatible with oral administration, in CT26 KRASG12C mutated cell lines and tumors. This is a first step towards the use of new combinatorial strategies using KRAS inhibitors and RT in KRASG12C mutated tumors, which are the most represented in NSCLC with 14% of patients harboring this mutational profile.© 2023. The Author(s).