Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Cell. 2021 Aug 5;184(16):4348-4371.e40. doi: 10.1016/j.cell.2021.07.016.
Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.
肺鳞状细胞癌（LSCC）仍然是癌症死亡的主要原因，治疗选择有限。我们对 LSCC 的蛋白质基因组景观进行了特征描述，为 LSCC 生物学提供了更深入的阐述，并具有潜在的治疗意义。我们确定 NSD3 是 FGFR1 扩增肿瘤和高表达治疗靶点 survivin 的低 p63 肿瘤的替代驱动因子。SOX2 被认为是不可成药的，但我们的分析为探索组蛋白修饰剂（如 LSD1 和 EZH2）以靶向 SOX2 过表达肿瘤提供了依据。我们的数据支持包括泛素化在内的翻译后修饰之间的相互作用对代谢途径的复杂调控。大量与免疫相关的蛋白质基因组观察结果为进一步研究提供了方向。CDKN2A 突变的蛋白质基因组分析表明，在宣布 CDK4/6 抑制失败之前，需要更细致地评估 RB1 蛋白表达和磷酸化。最后，LSCC、LUAD 和 HNSCC 之间的三角关系确定了独特和共同的治疗弱点。这些观察结果和蛋白质基因组数据资源可能指导对 LSCC 生物学和治疗的研究。
