Chan Cerise Yuen-Ki, Yuen Vincent Wai-Hin, Chiu David Kung-Chun, Goh Chi-Ching, Thu Kelsie L, Cescon David W, Soria-Bretones Isabel, Law Cheuk-Ting, Cheu Jacinth Wing-Sum, Lee Derek, Tse Aki Pui-Wah, Tan Kel Vin, Zhang Misty Shuo, Wong Bowie Po-Yee, Wong Chun-Ming, Khong Pek-Lan, Ng Irene Oi-Lin, Bray Mark R, Mak Tak Wah, Yau Thomas Chung-Cheung, Wong Carmen Chak-Lui
Department of Pathology , The University of Hong Kong , Hong Kong SAR , China.
Centre for Oncology and Immunology , Hong Kong Science Park , Hong Kong SAR , China.
Hepatology. 2023 Mar 1;77(3):729-744. doi: 10.1002/hep.32461. Epub 2023 Feb 17.
Prognosis of HCC remains poor due to lack of effective therapies. Immune checkpoint inhibitors (ICIs) have delayed response and are only effective in a subset of patients. Treatments that could effectively shrink the tumors within a short period of time are idealistic to be employed together with ICIs for durable tumor suppressive effects. HCC acquires increased tolerance to aneuploidy. The rapid division of HCC cells relies on centrosome duplication. In this study, we found that polo-like kinase 4 (PLK4), a centrosome duplication regulator, represents a therapeutic vulnerability in HCC.
An orally available PLK4 inhibitor, CFI-400945, potently suppressed proliferating HCC cells by perturbing centrosome duplication. CFI-400945 induced endoreplication without stopping DNA replication, causing severe aneuploidy, DNA damage, micronuclei formation, cytosolic DNA accumulation, and senescence. The cytosolic DNA accumulation elicited the DEAD box helicase 41-stimulator of interferon genes-interferon regulatory factor 3/7-NF-κβ cytosolic DNA sensing pathway, thereby driving the transcription of senescence-associated secretory phenotypes, which recruit immune cells. CFI-400945 was evaluated in liver-specific p53/phosphatase and tensin homolog knockout mouse HCC models established by hydrodynamic tail vein injection. Tumor-infiltrated immune cells were analyzed. CFI-400945 significantly impeded HCC growth and increased infiltration of cluster of differentiation 4-positive (CD4 + ), CD8 + T cells, macrophages, and natural killer cells. Combination therapy of CFI-400945 with anti-programmed death-1 showed a tendency to improve HCC survival.
We show that by targeting a centrosome regulator, PLK4, to activate the cytosolic DNA sensing-mediated immune response, CFI-400945 effectively restrained tumor progression through cell cycle inhibition and inducing antitumor immunity to achieve a durable suppressive effect even in late-stage mouse HCC.
由于缺乏有效的治疗方法，肝癌的预后仍然很差。免疫检查点抑制剂（ICIs）反应延迟，仅对一部分患者有效。能够在短时间内有效缩小肿瘤的治疗方法与ICIs联合使用以产生持久的肿瘤抑制效果是理想的。肝癌对非整倍体的耐受性增加。肝癌细胞的快速分裂依赖于中心体复制。在本研究中，我们发现中心体复制调节因子polo样激酶4（PLK4）是肝癌的一个治疗弱点。
一种口服可用的PLK4抑制剂CFI-400945，通过干扰中心体复制有效抑制增殖的肝癌细胞。CFI-400945诱导核内复制而不停止DNA复制，导致严重的非整倍体、DNA损伤、微核形成、胞质DNA积累和衰老。胞质DNA积累引发了DEAD盒解旋酶41-干扰素基因刺激因子-干扰素调节因子3/7-NF-κβ胞质DNA感应途径，从而驱动衰老相关分泌表型的转录，进而招募免疫细胞。在通过尾静脉注射建立的肝脏特异性p53/磷酸酶和张力蛋白同源物敲除小鼠肝癌模型中对CFI-400945进行了评估，并分析了肿瘤浸润免疫细胞。CFI-400945显著抑制肝癌生长，并增加了分化簇4阳性（CD4 +）、CD8 + T细胞、巨噬细胞和自然杀伤细胞的浸润。CFI-400945与抗程序性死亡1联合治疗显示出改善肝癌生存期的趋势。
我们表明通过靶向中心体调节因子PLK4来激活胞质DNA感应介导的免疫反应，CFI-400945通过抑制细胞周期和诱导抗肿瘤免疫有效抑制肿瘤进展，即使在晚期小鼠肝癌中也能实现持久的抑制作用。
