Department of Radiation Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California.
The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio.
Mol Cancer Res. 2022 Mar 1;20(3):425-433. doi: 10.1158/1541-7786.MCR-21-0272.
Lung squamous cell carcinoma (LUSC) accounts for one of three of non-small cell lung carcinoma (NSCLC) and 30% of LUSC patients present with locally advanced, unresectable/medically inoperable disease, who are commonly treated with definitive chemoradiation. However, disease relapse in the radiation fields occurs in one of three cases. We aim to explore the underlying molecular mechanisms of chemoradiation resistance of LUSC. Patient-derived xenograft (PDX) models of LUSC were established in immunodeficient mice, followed by treatment with cisplatin in combination with clinically relevant courses of ionizing radiation (20, 30, and 40 Gy). The recurrent tumors were extracted for functional proteomics using reverse phase protein analysis (RPPA). We found that phospho-AKT-S473, phospho-AKT-T308, phospho-S6-S235/6, and phospho-GSK3β-S9 were upregulated in the chemoradiation-resistant 20 Gy + cisplatin and 40 Gy + cisplatin tumors compared with those in the control tumors. Ingenuity pathway analysis of the RPPA data revealed that AKT-mTOR signaling was the most activated signaling pathway in the chemoradiation-resistant tumors. Similarly, elevated AKT-mTOR signaling was observed in stable 40 Gy and 60 Gy resistant HARA cell lines compared with the parental cell line. Accordingly, pharmacologic inhibition of mTOR kinase by Torin2 significantly sensitized LUSC cell lines to ionizing radiation. In conclusion, using chemoradiation-resistant PDX models coupled with RPPA proteomics analysis, we revealed that deregulation of AKT-mTOR signaling may contribute to the chemoradiation resistance of LUSC.
Clonal selection of subpopulations with high AKT-mTOR signaling in heterogeneous tumors may contribute to relapse of LUSC after chemoradiation. mTOR kinase inhibitors may be promising radiosensitizing agents in upfront treatment to prevent acquired resistance.
非小细胞肺癌（NSCLC）中约有三分之一为肺鳞状细胞癌（LUSC），30%的 LUSC 患者患有局部晚期、不可切除/不可手术的疾病，通常采用根治性放化疗治疗。然而，三分之一的患者在放射野中出现疾病复发。我们旨在探讨 LUSC 放化疗耐药的潜在分子机制。在免疫缺陷小鼠中建立了 LUSC 的患者来源异种移植（PDX）模型，然后用顺铂联合临床相关疗程的电离辐射（20、30 和 40 Gy）进行治疗。对复发性肿瘤进行反相蛋白分析（RPPA）的功能蛋白质组学提取。我们发现，与对照肿瘤相比，在耐 20 Gy + 顺铂和 40 Gy + 顺铂的肿瘤中，磷酸化 AKT-S473、磷酸化 AKT-T308、磷酸化 S6-S235/6 和磷酸化 GSK3β-S9 上调。RPPA 数据的 ingenuity 通路分析显示，AKT-mTOR 信号通路在耐放化疗肿瘤中最为活跃。同样，与亲本细胞系相比，稳定的 40 Gy 和 60 Gy 耐药 HARA 细胞系中也观察到 AKT-mTOR 信号的升高。因此，Torin2 抑制 mTOR 激酶的药理学抑制显著增强了 LUSC 细胞系对电离辐射的敏感性。总之，使用耐放化疗的 PDX 模型结合 RPPA 蛋白质组学分析，我们揭示了 AKT-mTOR 信号通路的失调可能导致 LUSC 放化疗后复发。mTOR 激酶抑制剂可能是治疗中预防获得性耐药的有前途的放射增敏剂。
异质性肿瘤中高 AKT-mTOR 信号亚群的克隆选择可能导致 LUSC 放化疗后复发。mTOR 激酶抑制剂可能是治疗中预防获得性耐药的有前途的放射增敏剂。
