Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
Cancer Biology Graduate Program, Emory University School of Medicine, Atlanta, Georgia.
Cancer Res Commun. 2022 Dec 6;2(12):1569-1578. doi: 10.1158/2767-9764.CRC-22-0158. eCollection 2022 Dec.
The high frequency of aberrant PI3K pathway activation in hormone receptor-positive (HR) breast cancer has led to the development, clinical testing, and approval of the p110α-selective PI3K inhibitor alpelisib. The limited clinical efficacy of alpelisib and other PI3K inhibitors is partially attributed to the functional antagonism between PI3K and estrogen receptor (ER) signaling, which is mitigated via combined PI3K inhibition and endocrine therapy. We and others have previously demonstrated chromatin-associated mechanisms by which PI3K supports cancer development and antagonizes ER signaling through the modulation of the H3K4 methylation axis, inhibition of KDM5A promoter H3K4 demethylation and KMT2D/MLL4-directed enhancer H3K4 methylation. Here we show that inhibition of the H3K4 histone methyltransferase MLL1 in combination with PI3K inhibition impairs HR breast cancer clonogenicity and cell proliferation. While combined PI3K/MLL1 inhibition reduces PI3K/AKT signaling and H3K4 methylation, MLL1 inhibition increases PI3K/AKT signaling through the dysregulation of gene expression associated with AKT activation. These data reveal a feedback loop between MLL1 and AKT whereby MLL1 inhibition reactivates AKT. We show that combined PI3K and MLL1 inhibition synergizes to cause cell death in and models of HR breast cancer, which is enhanced by the additional genetic ablation of the H3K4 methyltransferase and AKT target KMT2D/MLL4. Together, our data provide evidence of a feedback mechanism connecting histone methylation with AKT and may support the preclinical development and testing of pan-MLL inhibitors.
Here the authors leverage PI3K/AKT-driven chromatin modification to identify histone methyltransferases as a therapeutic target. Dual PI3K and MLL inhibition synergize to reduce clonogenicity and cell proliferation, and promote tumor regression. These findings suggest patients with PIK3CA-mutant, HR breast cancer may derive clinical benefit from combined PI3K/MLL inhibition.
PI3K 通路在激素受体阳性（HR）乳腺癌中的异常激活频率很高，这导致了 p110α 选择性 PI3K 抑制剂 alpelisib 的开发、临床测试和批准。alpelisib 和其他 PI3K 抑制剂的临床疗效有限，部分原因是 PI3K 与雌激素受体（ER）信号之间的功能拮抗作用，这种拮抗作用通过联合 PI3K 抑制和内分泌治疗来减轻。我们和其他人之前已经证明了染色质相关的机制，通过该机制，PI3K 通过调节 H3K4 甲基化轴、抑制 KDM5A 启动子 H3K4 去甲基化和 KMT2D/MLL4 定向增强子 H3K4 甲基化来支持癌症的发展并拮抗 ER 信号。在这里，我们表明，抑制组蛋白 H3K4 甲基转移酶 MLL1 与 PI3K 抑制联合使用会损害 HR 乳腺癌的集落形成能力和细胞增殖。虽然联合 PI3K/MLL1 抑制降低了 PI3K/AKT 信号和 H3K4 甲基化，但 MLL1 抑制通过 AKT 激活相关的基因表达失调增加了 PI3K/AKT 信号。这些数据揭示了 MLL1 和 AKT 之间的反馈回路，其中 MLL1 抑制使 AKT 重新激活。我们表明，联合 PI3K 和 MLL1 抑制协同作用导致 HR 乳腺癌 和 模型中的细胞死亡，当 H3K4 甲基转移酶和 AKT 靶标 KMT2D/MLL4 的遗传缺失进一步增强时，这种协同作用会增强。总的来说，我们的数据提供了连接组蛋白甲基化与 AKT 的反馈机制的证据，并且可能支持泛 MLL 抑制剂的临床前开发和测试。
在这里，作者利用 PI3K/AKT 驱动的染色质修饰来鉴定组蛋白甲基转移酶作为治疗靶标。双重 PI3K 和 MLL 抑制协同作用降低集落形成能力和细胞增殖，并促进肿瘤消退。这些发现表明，PIK3CA 突变的 HR 乳腺癌患者可能从联合 PI3K/MLL 抑制中获益。
