Tak Eunyoung, An Hye-In, Lee Amy Sinyoung, Han Kyuyoung, Choi Jiwan, Kim Hyung-Don, Hong Yong Sang, Kim Sun Young, Choi Eun Kyung, Kim Jeong Eun, Kim Tae Won
Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Department of Convergence Medicine, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Cancer Immunol Immunother. 2025 Mar 19;74(5):154. doi: 10.1007/s00262-025-04005-3.
BRAF-mutated colorectal cancer correlates with poor prognosis and limited response to standard treatments. Combining immune checkpoint inhibitors with BRAF/MEK inhibitors shows promise against BRAF-mutant melanoma in both preclinical and clinical trials. Therefore, we hypothesized that the treatment would be effective against BRAF-mutant colorectal cancer. In this study, we assessed the efficacy of combining immune checkpoint inhibitors with BRAF and/or MEK inhibitors in BRAF-mutant colorectal cancers. We treated BRAF V600E colorectal cancer cells HT-29 and SNU-1235 with encorafenib (BRAF inhibitor) and binimetinib (MEK inhibitor) and assessed the degrees of MAPK inhibition, JAK/STAT inhibition, cell viability, apoptosis, and the expression of antigen presenting machinery. We also inoculated HT-29 cells into mice and treated them with an immune checkpoint inhibitor (durvalumab), encorafenib, and binimetinib for 4 weeks. We found that treatment with BRAF inhibitor, MEK inhibitor, or their combination led to significant tumor growth reduction, along with the MAPK and JAK/STAT pathway inhibition, antigen presenting machinery induction, and cytotoxic T cell activation. Our study demonstrates the potential effectiveness of combining immune checkpoint inhibitors with BRAF or MEK inhibitors for BRAF-mutated colorectal cancers.
BRAF 突变型结直肠癌与预后不良以及对标准治疗反应有限相关。在临床前和临床试验中，将免疫检查点抑制剂与 BRAF/MEK 抑制剂联合使用对 BRAF 突变型黑色素瘤显示出前景。因此，我们假设该治疗对 BRAF 突变型结直肠癌有效。在本研究中，我们评估了在 BRAF 突变型结直肠癌中联合使用免疫检查点抑制剂与 BRAF 和/或 MEK 抑制剂的疗效。我们用恩考芬尼（BRAF 抑制剂）和比美替尼（MEK 抑制剂）处理 BRAF V600E 结直肠癌细胞 HT-29 和 SNU-1235，并评估 MAPK 抑制、JAK/STAT 抑制、细胞活力、凋亡以及抗原呈递机制的表达程度。我们还将 HT-29 细胞接种到小鼠体内，并用免疫检查点抑制剂（度伐利尤单抗）、恩考芬尼和比美替尼处理 4 周。我们发现，用 BRAF 抑制剂、MEK 抑制剂或它们的组合进行治疗可显著降低肿瘤生长，同时抑制 MAPK 和 JAK/STAT 途径、诱导抗原呈递机制并激活细胞毒性 T 细胞。我们的研究证明了将免疫检查点抑制剂与 BRAF 或 MEK 抑制剂联合用于 BRAF 突变型结直肠癌的潜在有效性。
