PO.CL07.03 · 临床研究
一种克服肺癌代谢重编程的新型治疗方法
A novel therapeutic approach to overcome metabolic reprogramming in lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肺癌仍然是癌症相关死亡的首要原因。基因组研究已经确定，SWI/SNF染色质重塑复合物亚基中频繁存在突变，尤其是在非小细胞肺癌中的SMARCA4和ARID1A，突变发生率在晚期病例中高达33%。此前我们已经证明，SMARCA4突变型肺癌高度依赖氧化磷酸化（OXPHOS）。然而，OXPHOS抑制剂作为单药在临床试验中未能显示出实质性疗效。因此，与其他针对癌症代谢的治疗方法一样，进一步开发OXPHOS抑制剂最可行的途径是通过合理的联合策略。为此，我们利用靶向具有FDA批准治疗药物的基因的CRISPR-Cas9文库，在基因定义明确的肺癌模型中进行了功能基因组学筛选。重要的是，我们使用了已知在患者中耐受性良好的极低剂量OXPHOS抑制剂IACS-10759。在我们的最佳命中结果中就有ROCK1/2。我们证明，Belumosudil是一种临床应用的ROCK抑制剂，以其强大的安全性和耐受性著称，当与IACS-10759联合使用时，在细胞系以及多个小鼠异种移植和人类PDX模型中表现出显著的协同抗肿瘤活性。在机制上，代谢分析显示，ROCK和OXPHOS抑制的联合触发了生物能量应激和细胞周期阻滞。这主要归因于抑制了OXPHOS抑制后发生的糖酵解适应性增加，其机制是ROCK通过抑制GLUT1介导的葡萄糖摄取。通过定量蛋白质组学、磷酸化蛋白质组学和激酶基序分析，我们鉴定出几种直接的ROCK底物，包括在肌动蛋白细胞骨架调控和葡萄糖转运中起关键作用的PPP1R12A和PPP1R12C。综上所述，我们阐明了一种高度协同的联合策略的机制基础，该策略克服了适应性代谢重编程——这一直是成功开发靶向癌症代谢的治疗方法的核心挑战。
查看英文原文 English abstract
Lung cancer remains the leading cause of cancer-related deaths. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex, particularly in SMARCA4 and ARID1A , in non-small cell lung cancer, with mutations occurring in up to 33% of advanced cases. Previously we have shown that SMARCA4 -mutant lung cancers are highly dependent on oxidative phosphorylation (OXPHOS). However, OXPHOS inhibitors as single agents have failed to show substantial efficacy in clinical trials. Thus, like other therapeutics aimed at cancer metabolism, the most feasible route for further development of OXPHOS inhibitors is through rational combination strategies. To this end, we undertook a functional genomics screen to identify combination strategies by utilizing a CRISPR-Cas9 library targeting genes with FDA approved therapeutics in genetically defined lung cancer models. Importantly, we utilized very low doses of the OXPHOS inhibitor IACS-10759 that are known to be well-tolerated in patients. Among our top hits was ROCK1/2. We show that Belumosudil, a clinically-utilized ROCK inhibitor known for its robust safety and tolerability profile, exhibits profound synergistic anti-tumor activity when combined with IACS-10759 in cell lines as well as in multiple mouse xenograft and human PDX models. Mechanistically, metabolic profiling reveals that the combination of ROCK and OXPHOS inhibition triggers bioenergetic stress and cell cycle arrest. This is primarily attributed to the inhibition of the adaptive increase in glycolysis that occurs following OXPHOS inhibition by ROCK, via suppression of GLUT1-mediated glucose uptake. Through quantitative proteomics, phospho-proteomics and kinase motif analysis, we identified several direct ROCK substrates including PPP1R12A and PPP1R12C that play critical roles in actin cytoskeleton regulation and glucose transport. Taken together, we identified the mechanistic underpinnings of a highly synergistic combination strategy that overcomes adaptive metabolic reprograming which has been a central challenge in the successful development of therapeutics targeting cancer metabolism.
利益披露 Disclosure
N. Blazanin, None..
X. Liang, None..
Y. Lissanu, None.