PDF(Pubmed)
Abstract：
The comprehensive genomic analysis of the head and neck squamous cell carcinoma (HNSCC) oncogenome revealed the frequent loss of p16INK4A (CDKN2A) and amplification of cyclin D1 genes in most human papillomavirus-negative HNSCC lesions. However, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown modest effects in the clinic. The aberrant activation of the PI3K/mTOR pathway is highly prevalent in HNSCC, and recent clinical trials have shown promising clinical efficacy of mTOR inhibitors (mTORi) in the neoadjuvant and adjuvant settings but not in patients with advanced HNSCC. By implementing a kinome-wide CRISPR/Cas9 screen, we identified cell-cycle inhibition as a synthetic lethal target for mTORis. A combination of mTORi and palbociclib, a CDK4/6-specific inhibitor, showed strong synergism in HNSCC-derived cells in vitro and in vivo. Remarkably, we found that an adaptive increase in cyclin E1 (CCNE1) expression upon palbociclib treatment underlies the rapid acquired resistance to this CDK4/6 inhibitor. Mechanistically, mTORi inhibits the formation of eIF4G-CCNE1 mRNA complexes, with the consequent reduction in mRNA translation and CCNE1 protein expression. Our findings suggest that mTORi reverts the adaptive resistance to palbociclib. This provides a multimodal therapeutic option for HNSCC by cotargeting mTOR and CDK4/6, which in turn may halt the emergence of palbociclib resistance.
UNASSIGNED: A kinome-wide CRISPR/Cas9 screen identified cell-cycle inhibition as a synthetic lethal target of mTORis. A combination of mTORi and palbociclib, a CDK4/6-specific inhibitor, showed strong synergistic effects in HNSCC. Mechanistically, mTORis inhibited palbociclib-induced increase in CCNE1.
UNASSIGNED: A kinome-wide CRISPR/Cas9 screen identified cell-cycle inhibition as a synthetic lethal target of mTORis. A combination of mTORi and palbociclib, a CDK4/6-specific inhibitor, showed strong synergistic effects in HNSCC. Mechanistically, mTORis inhibited palbociclib-induced increase in CCNE1.
摘要：
头颈部鳞状细胞癌（HNSCC）癌基因组的综合基因组分析显示，在大多数HPV阴性的HNSCC病变中，p16INK4A（CDKN2A）的频繁丢失和细胞周期蛋白D1（CCND1）基因的扩增。然而,细胞周期蛋白依赖性激酶4和6（CDK4/6）抑制剂在临床上显示出适度的作用。PI3K/mTOR通路的异常激活在HNSCC中非常普遍，最近的临床试验显示mTOR抑制剂（mTORi）在新辅助和辅助治疗中具有良好的临床疗效，但在晚期HNSCC患者中无效。通过kinome宽的CRISPR/Cas9屏幕，我们确定细胞周期抑制是mTORi的合成致死靶标.mTORi和palbociclib的组合，CDK4/6特异性抑制剂，在体外和体内HNSCC来源的细胞中显示出强的协同作用。值得注意的是,我们发现palbociclib治疗后细胞周期蛋白E1(CCNE1)表达的适应性增加是对该CDK4/6抑制剂快速获得性耐药的基础.机械上,mTORi抑制eIF4G-CCNE1mRNA复合物的形成，随着mRNA翻译和CCNE1蛋白表达的减少。我们的发现表明mTORi恢复了对palbociclib的适应性抗性。这通过共同靶向mTOR和CDK4/6为HNSCC提供了多模式治疗选择，这反过来可能会阻止palbociclib耐药性的出现。
