Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
Proteomics Facility, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
Nat Commun. 2019 May 2;10(1):2030. doi: 10.1038/s41467-019-09438-w.
Acquired resistance to MEK1/2 inhibitors (MEKi) arises through amplification of BRAF or KRAS to reinstate ERK1/2 signalling. Here we show that BRAF amplification and MEKi resistance are reversible following drug withdrawal. Cells with BRAF amplification are addicted to MEKi to maintain a precise level of ERK1/2 signalling that is optimal for cell proliferation and survival, and tumour growth in vivo. Robust ERK1/2 activation following MEKi withdrawal drives a p57-dependent G1 cell cycle arrest and senescence or expression of NOXA and cell death, selecting against those cells with amplified BRAF. p57 expression is required for loss of BRAF amplification and reversal of MEKi resistance. Thus, BRAF amplification confers a selective disadvantage during drug withdrawal, validating intermittent dosing to forestall resistance. In contrast, resistance driven by KRAS amplification is not reversible; rather ERK1/2 hyperactivation drives ZEB1-dependent epithelial-to-mesenchymal transition and chemoresistance, arguing strongly against the use of drug holidays in cases of KRAS amplification.
MEK1/2 抑制剂（MEKi）获得性耐药是通过 BRAF 或 KRAS 的扩增来重新激活 ERK1/2 信号。在这里，我们表明 BRAF 扩增和 MEKi 耐药性在停药后是可逆的。具有 BRAF 扩增的细胞依赖 MEKi 来维持精确的 ERK1/2 信号水平，这对于细胞增殖和存活以及体内肿瘤生长是最佳的。MEKi 停药后强大的 ERK1/2 激活会导致 p57 依赖性 G1 细胞周期停滞和衰老或 NOXA 的表达和细胞死亡，从而选择那些具有扩增 BRAF 的细胞。p57 的表达对于 BRAF 扩增的丧失和 MEKi 耐药性的逆转是必需的。因此，BRAF 扩增在停药期间赋予了选择性劣势，验证了间歇性给药以阻止耐药性的产生。相比之下，由 KRAS 扩增驱动的耐药性是不可逆转的；相反，ERK1/2 的过度激活会驱动 ZEB1 依赖性上皮间质转化和化疗耐药性，这强烈反对在 KRAS 扩增的情况下使用药物假期。
