Abstract：
Colorectal cancer (CRC) is a common malignant tumor with a high incidence and mortality worldwide. Preoperative chemoradiotherapy is a common treatment for patients with metastatic colorectal cancer (mCRC) as it reduces colostomy and local recurrence. The RAS (rat sarcoma)-RAF (extracellular signal-regulated kinase)-MEK (mitogen-activated protein kinase)-ERK (extracellular signal-regulated kinase) pathway regulates important cellular processes in the CRC. Abnormal ERK activation stimulates cell growth and provides a survival advantage. Our group has previously reported that the compound KZ02 has a stronger ability to inhibit tumor growth than AZD6244 (a MEK inhibitor). In this study, we evaluated the antitumor activity of KZ02 in combination with ionizing radiation (IR) and investigated its mechanism of action in BRAF-mutated colorectal cancer. Our results showed that this combination kills tumor cells better than either radiation or drugs alone, both in vivo and in vitro. Furthermore, studies have shown that KZ02 inhibits ERK overactivation. The combination resulted in a G1 phase arrest, a reduction in the radioresistant S phase, and aggravating DNA damage. It can also inhibit Pim-1 (Moloney murine leukemia virus-1), p-BAD (Bcl-2 associated agonist of cell death), Bcl-2 (B-cell lymphoma 2) and Bcl-XL (B-cell lymphoma-extra large) levels and promote apoptosis when combined with radiation. Our results suggest that KZ02 significantly increases the radiosensitivity of BRAF-mutated CRC cells by perturbing the cell cycle, increasing DNA damage, and promoting tumor apoptosis.
摘要：
结直肠癌(CRC)是世界范围内常见的恶性肿瘤,具有较高的发病率和死亡率。术前放化疗是转移性结直肠癌（mCRC）患者的常用治疗方法，因为它可以减少结肠造口和局部复发。RAS(大鼠肉瘤)-RAF(细胞外信号调节激酶)-MEK(丝裂原活化蛋白激酶)-ERK(细胞外信号调节激酶)途径调节CRC中的重要细胞过程。异常的ERK活化刺激细胞生长并提供存活优势。我们小组先前报道化合物KZ02比AZD6244(MEK抑制剂)具有更强的抑制肿瘤生长的能力。在这项研究中,我们评估了KZ02联合电离辐射（IR）的抗肿瘤活性，并研究了其在BRAF突变的结直肠癌中的作用机制。我们的结果表明，这种组合比单独的辐射或药物更好地杀死肿瘤细胞，体内和体外。此外，研究表明KZ02抑制ERK过度激活。组合导致G1期停滞，抗辐射S阶段的减少，并加重DNA损伤.它还可以抑制Pim-1（莫洛尼鼠白血病病毒-1），p-BAD（Bcl-2相关的细胞死亡激动剂），Bcl-2（B细胞淋巴瘤2）和Bcl-XL（B细胞淋巴瘤-超大）水平，并促进细胞凋亡时，结合辐射。我们的结果表明，KZ02通过扰乱细胞周期显着增加BRAF突变的CRC细胞的放射敏感性，增加DNA损伤,促进肿瘤细胞凋亡。
