Wnt/β-Catenin Pathway Activation Mediates Adaptive Resistance to BRAF Inhibition in Colorectal Cancer.
Wnt/β-Catenin Pathway Activation Mediates Adaptive Resistance to BRAF Inhibition in Colorectal Cancer.
复制标题
Wnt/β-Catenin通路激活介导了结直肠癌对BRAF抑制的适应性抵抗。
DOI：
10.1158/1535-7163.mct-17-0561
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发表时间：
2018-04
影响因子：
5.7
通讯作者：
Hu J
中科院分区：
文献类型：
--
作者：
Chen G;Gao C;Gao X;Zhang DH;Kuan SF;Burns TF;Hu J
肿瘤学中最令人鼓舞的进展之一是BRAF抑制剂在BRAF突变型黑色素瘤中的成功。然而，与其在BRAF突变型黑色素瘤中的显著功效相反，BRAF抑制剂单一疗法在BRAF突变型结直肠癌（CRC）中无效。虽然许多关于CRC中BRAF抑制剂耐药的研究都集中在EGFR/RAS/RAF/MEK/ERK通路重新激活的机制上，但目前的研究重点是确定新的适应性信号传导机制，这是CRC对BRAF抑制耐药的新角度。我们发现用BRAF抑制剂（当前和下一代BRAF抑制剂）处理通过激活细胞质酪氨酸激酶FAK（粘着斑激酶）上调BRAFV 600 E突变CRC细胞系中的Wnt/β-连环蛋白途径。结果显示，BRAF抑制剂处理后FAK活化不需要EGFR（表皮生长因子受体）或ERK 1/2（细胞外信号调节激酶1/2）活化，这意味着BRAF抑制剂处理诱导的Wnt信号传导过度活化是“途径再活化”独立的。在BRAFV 600 E突变型CRC的临床前模型（包括细胞系异种移植模型和PDX（患者来源的异种移植）模型）中进一步验证了BRAF抑制诱导的Wnt途径活化。联合抑制BRAF/Wnt通路或BRAF/FAK通路在细胞培养模型和小鼠异种移植模型中表现出强烈的协同抗肿瘤作用。总体而言，目前的研究已经确定Wnt/β-连环蛋白途径的激活是结肠癌对BRAF抑制耐药的新的根本原因。我们的研究结果表明，虽然完全的垂直通路阻断对于BRAF突变型CRC的有效和持久控制至关重要，但共同靶向平行适应性信号传导-Wnt/β-连环蛋白通路-也是必不可少的。
One of the most encouraging developments in oncology has been the success of BRAF inhibitors in BRAF-mutant melanoma. However, in contrast to its striking efficacy in BRAF-mutant melanomas, BRAF inhibitor monotherapy is ineffective in BRAF-mutant colorectal cancer (CRC). While many studies on BRAF inhibitor resistance in CRC have focused on mechanisms underlying the reactivation of the EGFR/RAS/RAF/MEK/ERK pathway, the current study focuses on identifying novel adaptive signaling mechanisms, a fresh angle on CRC resistance to BRAF inhibition. We found that treatment with BRAF inhibitors (both current and next generation BRAF inhibitors) upregulated the Wnt/β-catenin pathway in BRAFV600E-mutant CRC cell lines through activating the cytoplasmic tyrosine kinase FAK (focal adhesion kinase). The results showed that FAK activation upon BRAF inhibitor treatment did not require EGFR (Epidermal Growth Factor Receptor) or ERK1/2 (extracellular-signal-regulated kinases1/2) activation, implying that BRAF inhibitor treatment-induced hyperactivation of Wnt signaling is “pathway reactivation”-independent. BRAF inhibition-induced Wnt pathway activation was further validated in preclinical models of BRAFV600E-mutant CRC including cell line xenograft model and a PDX (patient-derived xenograft) model. Combined inhibition of BRAF/Wnt pathways or BRAF/FAK pathways exerted strong synergistic antitumor effects in cell culture model and mouse xenograft model. Overall, the current study has identified activation of the Wnt/β-catenin pathway as a novel fundamental cause of colon cancer resistance to BRAF inhibition. Our results suggest that while complete vertical pathway blockade is pivotal for effective and durable control of BRAF-mutant CRC, co-targeting parallel adaptive signaling—the Wnt/β-catenin pathway—is also essential.