PO.MCB03.01 · 分子与细胞生物学
抑制mTOR通过一个新的AKT启动的反馈环激活EGFR-MAPK网络，促进适应性耐药
mTOR inhibition activates the EGFR-MAPK network by a novel AKT-initiated feedback loop promoting adaptive resistance
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摘要 Abstract
中文摘要
头颈部鳞状细胞癌（HNSCC）是全球第六大常见癌症，每年在全球导致超过300,000人死亡。HNSCC患者的治疗选择包括手术、放疗、化疗和分子靶向治疗，尽管免疫治疗近来彻底改变了治疗格局，但仅有<20%的HNSCC患者对免疫检查点阻断（ICB）疗法产生应答。过去数十年间，HNSCC患者的生存率仅有微小改善，因此HNSCC是一个高死亡率和高发病率的重大全球健康问题。汇聚于PI3K/mTOR通路持续激活的基因组改变（>80%的病例）是HNSCC中最常发生改变的信号回路之一。这种对PI3K/mTOR信号促进肿瘤生长的过度依赖可能暴露出一种可被治疗利用的癌症脆弱性，正如近期mTOR抑制剂（mTORi）在HNSCC辅助和新辅助治疗中的临床试验所揭示的那样。然而，mTORi对晚期HNSCC患者无效，凸显了阐明mTORi耐药机制的紧迫性。通过结合系统生物学与计算方法的力量，包括高通量激酶活性图谱策略、CRISPR/Cas9合成致死筛选、CRISPR引导的内源性EGFR的GFP标记，以及对细胞内ERK库时空激活的分析，我们现已确定mTORi在HNSCC中诱导的EGFR-MAPK信号激活是一条主要的适应性代偿耐药通路。在机制上，我们发现抑制mTOR通过破坏一个新的AKT调控的、使EGFR失活的反馈环，从而激活EGFR-MAPK通路。最终，我们的发现表明，EGFR的适应性激活代表了一种新的mTORi耐药机制，且共同靶向EGFR可能是HNSCC的一个有效治疗选择。这些发现可能与大量依赖PI3K/mTOR信号但对mTORi单药治疗无应答的癌症类型相关。
查看英文原文 English abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally, resulting in more than 300,000 deaths each year worldwide. Treatment options for HNSCC patients include surgery, radiation, chemotherapy, and molecularly targeted therapies, and although immunotherapies have recently revolutionized the treatment landscape, <20% of HNSCC patients respond to immune checkpoint blockade (ICB) therapies. The survival rate of HNSCC patients has changed only modestly over the past decades, and therefore, HNSCC is a significant global health problem with high mortality and morbidity. Genomic alterations converging on persistent activation of the PI3K/mTOR pathway (>80% of cases) represent one of the most frequently altered signaling circuits in HNSCC. This overreliance on PI3K/mTOR signaling for tumor growth may expose a cancer vulnerability that can be therapeutically exploited, as revealed by recent clinical trials of mTOR inhibitors (mTORi) in HNSCC in the adjuvant and neoadjuvant settings. However, mTORi are ineffective in patients with advanced HNSCC, highlighting the urgency of elucidating the mechanisms underlying mTORi resistance. By combining the power of systems biology and computational approaches, including a high-throughput kinase activity mapping strategy, CRISPR/Cas9 synthetic lethal screening, CRISPR-guided GFP-tagging of endogenous EGFR, and the analysis of the spatiotemporal activation of intracellular ERK pools, we have now identified the activation of EGFR-MAPK signaling induced by mTORi in HNSCC as a major adaptive compensatory resistance pathway. Mechanistically, we found that mTOR inhibition activates the EGFR-MAPK pathway by disrupting a novel AKT-regulated feedback loop that inactivates EGFR. Ultimately, our findings suggest that the adaptive activation of EGFR represents a new mechanism of mTORi resistance, and that EGFR co-targeting may be a potent therapeutic option for HNSCC. These findings may be relevant to a large number of cancer types that depend on PI3K/mTOR signaling but fail to respond to mTORi therapies as single agents.
利益披露 Disclosure
K. Koshizuka, None..
T. Ishikawa, None..
K. Sato, None..
J. Gutkind, None.