Current treatments for KRAS-mutant colorectal cancers (CRCs) are often limited by cellular plasticity and rewiring responses. Here we describe a promising therapeutic strategy that simultaneously targets epigenetic and oncogenic signals. Specifically, we show that inhibitors of the histone methyltransferase, EZH2, synergize with various RAS pathway inhibitors and promote dramatic tumor regression in vivo. Together these agents cooperatively suppress WNT-driven transcription and drive CRCs into a more differentiated cell state by inducing the Groucho/TLE corepressor, TLE4, along with a network of WNT pathway inhibitors and intestinal differentiation proteins. However, these agents also induce the pro-apoptotic protein BMF, which subsequently kills these more differentiated cells. Accordingly, cell death can be prevented by activating β-catenin, blocking differentiation, or by ablating BMF expression. Collectively, these studies reveal a new therapeutic approach for treating KRAS-mutant CRCs and illustrate a critical convergence of EZH2 and RAS on oncogenic WNT signals, intestinal differentiation, and apoptosis.

中文翻译：

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表观遗传学和致癌抑制剂协同驱动分化并杀死 KRAS 突变型结直肠癌


目前对 KRAS 突变结直肠癌 （CRC） 的治疗通常受到细胞可塑性和重新布线反应的限制。在这里，我们描述了一种有前途的治疗策略，该策略同时靶向表观遗传和致癌信号。具体来说，我们表明组蛋白甲基转移酶 EZH2 的抑制剂与各种 RAS 通路抑制剂协同作用，并在体内促进肿瘤显着消退。这些药物共同协同抑制 WNT 驱动的转录，并通过诱导 Groucho/TLE 辅阻遏蛋白 TLE4 以及 WNT 通路抑制剂和肠分化蛋白网络，将 CRC 驱动到分化程度更高的细胞状态。然而，这些药物也会诱导促凋亡蛋白 BMF，从而杀死这些分化程度更高的细胞。因此，可以通过激活 β-catenin、阻断分化或消融 BMF 表达来防止细胞死亡。总的来说，这些研究揭示了一种治疗 KRAS 突变 CRC 的新治疗方法，并说明了 EZH2 和 RAS 在致癌 WNT 信号、肠道分化和细胞凋亡方面的关键收敛。