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. Although many studies on BRAF inhibitor resistance in colorectal cancer 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 colorectal cancer 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 colorectal cancer cell lines through activating the cytoplasmic tyrosine kinase focal adhesion kinase (FAK). The results showed that FAK activation upon BRAF inhibitor treatment did not require EGFR or ERK1/2 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 colorectal cancer, including cell line xenograft model and a 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 although complete vertical pathway blockade is pivotal for effective and durable control of BRAF-mutant colorectal cancer, cotargeting parallel adaptive signaling—the Wnt/β-catenin pathway—is also essential. Mol Cancer Ther; 17(4); 806–13. ©2017 AACR.

中文翻译：

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Wnt/β-catenin通路激活介导结直肠癌对BRAF抑制的适应性抵抗

肿瘤学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着疗效相反，BRAF 抑制剂单药治疗对 BRAF 突变型结直肠癌无效。尽管许多关于结直肠癌 BRAF 抑制剂耐药性的研究都集中在 EGFR/RAS/RAF/MEK/ERK 通路重新激活的潜在机制上，但目前的研究重点是确定新的适应性信号机制，这是结直肠癌对 BRAF 耐药性的一个新角度抑制。我们发现用 BRAF 抑制剂（当前和下一代 BRAF 抑制剂）治疗通过激活细胞质酪氨酸激酶粘着斑激酶 (FAK) 上调 BRAFV600E 突变结直肠癌细胞系中的 Wnt/β-连环蛋白通路。结果表明，BRAF 抑制剂治疗后的 FAK 激活不需要 EGFR 或 ERK1/2 激活，这意味着 BRAF 抑制剂治疗诱导的 Wnt 信号过度激活是“通路再激活”独立的。BRAF 抑制诱导的 Wnt 通路激活在 BRAFV600E 突变结直肠癌的临床前模型中得到进一步验证，包括细胞系异种移植模型和患者来源的异种移植模型。BRAF/Wnt 通路或 BRAF/FAK 通路的联合抑制在细胞培养模型和小鼠异种移植模型中发挥了强大的协同抗肿瘤作用。总体而言，目前的研究已将 Wnt/β-catenin 通路的激活确定为结肠癌对 BRAF 抑制耐药的新根本原因。我们的结果表明，虽然完全垂直通路阻断对于有效和持久控制 BRAF 突变型结直肠癌至关重要，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。摩尔癌症治疗; 17(4); 806-13。©2017 AACR。