尽管数十种基因靶向癌症疗法在临床上取得了成功，但绝大多数因功能丧失（LoF）突变引起的肿瘤患者无法获得这些治疗。这主要是由于开发一种药物来治疗由于缺乏蛋白质靶点而引起的疾病所面临的挑战。 PARP 抑制剂的成功巩固了合成致死 (SL) 作为克服这一障碍的手段。最近使用汇集的 CRISPR-Cas9 屏幕绘制 SL 网络图谱是一种很有前景的方法，可以将这一概念扩展到治疗由其他 LoF 驱动因素驱动的癌症。然而，在实践中，将通常进行这些筛选的细胞系的信号转化为患者的结果仍然是一个挑战。我们开发了一种称为“临床优化驱动相关-PGx”(CODA-PGX) 的药物基因组 (PGx) 方法，该方法可准确预测特定 LoF 驱动环境中具有临床阶段疗效的基因靶向疗法。使用已批准的靶向治疗和癌症药物以及来自数百名患者的可用真实世界证据和分子数据，我们发现并优化了预测疗效和患者总体生存率的关键筛选原则。除了建立基本的技术惯例（例如药物浓度和筛选动力学）之外，我们发现在正确的环境中复制驱动扰动以及选择这些驱动驱动是真正的创始人突变的患者是准确翻译的关键。我们使用 CODA-PGX 筛选了多种临床阶段药物，并报告了数十种新颖的 LoF 基因靶向机会；许多在异种移植和现实世界的证据中得到验证。值得注意的例子包括用卡铂治疗 STAG2 突变肿瘤、用奥沙利铂治疗 SMARCB1 突变肿瘤以及用依托泊苷或博莱霉素治疗 TP53BP1 突变肿瘤。© 2024。作者。

Despite the clinical success of dozens of genetically targeted cancer therapies, the vast majority of patients with tumors caused by loss-of-function (LoF) mutations do not have access to these treatments. This is primarily due to the challenge of developing a drug that treats a disease caused by the absence of a protein target. The success of PARP inhibitors has solidified synthetic lethality (SL) as a means to overcome this obstacle. Recent mapping of SL networks using pooled CRISPR-Cas9 screens is a promising approach for expanding this concept to treating cancers driven by additional LoF drivers. In practice, however, translating signals from cell lines, where these screens are typically conducted, to patient outcomes remains a challenge. We developed a pharmacogenomic (PGx) approach called "Clinically Optimized Driver Associated-PGx" (CODA-PGX) that accurately predicts genetically targeted therapies with clinical-stage efficacy in specific LoF driver contexts. Using approved targeted therapies and cancer drugs with available real-world evidence and molecular data from hundreds of patients, we discovered and optimized the key screening principles predictive of efficacy and overall patient survival. In addition to establishing basic technical conventions, such as drug concentration and screening kinetics, we found that replicating the driver perturbation in the right context, as well as selecting patients where those drivers are genuine founder mutations, were key to accurate translation. We used CODA-PGX to screen a diverse collection of clinical stage drugs and report dozens of novel LoF genetically targeted opportunities; many validated in xenografts and by real-world evidence. Notable examples include treating STAG2-mutant tumors with Carboplatin, SMARCB1-mutant tumors with Oxaliplatin, and TP53BP1-mutant tumors with Etoposide or Bleomycin.© 2024. The Author(s).