Thng Dexter Kai Hao, Toh Tan Boon, Pigini Paolo, Hooi Lissa, Dan Yock Young, Chow Pierce Kah-Hoe, Bonney Glenn Kunnath, Rashid Masturah Bte Mohd Abdul, Guccione Ernesto, Wee Dave Keng Boon, Chow Edward Kai-Hua
Cancer Science Institute of Singapore, National University of Singapore Singapore Singapore.
The N.1 Institute for Health, National University of Singapore Singapore Singapore.
Bioeng Transl Med. 2022 Sep 3;8(1):e10363. doi: 10.1002/btm2.10363. eCollection 2023 Jan.
Deregulation of MYC is among the most frequent oncogenic drivers in hepatocellular carcinoma (HCC). Unfortunately, the clinical success of MYC-targeted therapies is limited. Synthetic lethality offers an alternative therapeutic strategy by leveraging on vulnerabilities in tumors with MYC deregulation. While several synthetic lethal targets of MYC have been identified in HCC, the need to prioritize targets with the greatest therapeutic potential has been unmet. Here, we demonstrate that by pairing splice-switch oligonucleotide (SSO) technologies with our phenotypic-analytical hybrid multidrug interrogation platform, quadratic phenotypic optimization platform (QPOP), we can disrupt the functional expression of these targets in specific combinatorial tests to rapidly determine target-target interactions and rank synthetic lethality targets. Our SSO-QPOP analyses revealed that simultaneous attenuation of CHK1 and BRD4 function is an effective combination specific in MYC-deregulated HCC, successfully suppressing HCC progression in vitro. Pharmacological inhibitors of CHK1 and BRD4 further demonstrated its translational value by exhibiting synergistic interactions in patient-derived xenograft organoid models of HCC harboring high levels of MYC deregulation. Collectively, our work demonstrates the capacity of SSO-QPOP as a target prioritization tool in the drug development pipeline, as well as the therapeutic potential of CHK1 and BRD4 in MYC-driven HCC.
MYC失调是肝细胞癌（HCC）中最常见的致癌驱动因素之一。不幸的是，针对MYC的治疗在临床上取得的成功有限。合成致死性通过利用MYC失调肿瘤中的脆弱性提供了一种替代治疗策略。虽然在HCC中已经确定了几个MYC的合成致死靶点，但尚未满足对具有最大治疗潜力的靶点进行优先级排序的需求。在这里，我们证明，通过将剪接开关寡核苷酸（SSO）技术与我们的表型分析混合多药询问平台——二次表型优化平台（QPOP）相结合，我们可以在特定的组合测试中破坏这些靶点的功能表达，以快速确定靶点-靶点相互作用并对合成致死靶点进行排名。我们的SSO-QPOP分析表明，同时减弱CHK1和BRD4的功能是一种在MYC失调的HCC中特异的有效组合，在体外成功抑制了HCC的进展。CHK1和BRD4的药理抑制剂在具有高水平MYC失调的HCC患者来源的异种移植类器官模型中表现出协同相互作用，进一步证明了其转化价值。总的来说，我们的工作证明了SSO-QPOP作为药物开发流程中靶点优先级排序工具的能力，以及CHK1和BRD4在MYC驱动的HCC中的治疗潜力。
