Colorectal cancer is the third most common cancer in the United States and responsible for over 50,000 deaths each year. Therapeutic options for advanced colorectal cancer are limited, and there remains an unmet clinical need to identify new treatments for this deadly disease. To address this need, we developed a precision medicine pipeline that integrates high-throughput chemical screens with matched patient-derived cell lines and patient-derived xenografts (PDX) to identify new treatments for colorectal cancer. High-throughput screens of 2,100 compounds were performed across six low-passage, patient-derived colorectal cancer cell lines. These screens identified the CDK inhibitor drug class among the most effective cytotoxic compounds across six colorectal cancer lines. Among this class, combined targeting of CDK1, 2, and 9 was the most effective, with IC50s ranging from 110 nmol/L to 1.2 μmol/L. Knockdown of CDK9 in the presence of a CDK2 inhibitor (CVT-313) showed that CDK9 knockdown acted synergistically with CDK2 inhibition. Mechanistically, dual CDK2/9 inhibition induced significant G2–M arrest and anaphase catastrophe. Combined CDK2/9 inhibition in vivo synergistically reduced PDX tumor growth. Our precision medicine pipeline provides a robust screening and validation platform to identify promising new cancer therapies. Application of this platform to colorectal cancer pinpointed CDK2/9 dual inhibition as a novel combinatorial therapy to treat colorectal cancer.

中文翻译：

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一个精准医学药物发现管道确定联合 CDK2 和 9 抑制作为结直肠癌的新治疗策略

结直肠癌是美国第三大常见癌症，每年导致超过 50,000 人死亡。晚期结直肠癌的治疗选择是有限的，并且仍有未满足的临床需求来确定这种致命疾病的新疗法。为了满足这一需求，我们开发了一种精准医学管道，将高通量化学筛选与匹配的患者来源细胞系和患者来源异种移植物 (PDX) 相结合，以确定结直肠癌的新疗法。对 2,100 种化合物的高通量筛选在六个低通道、患者来源的结肠直肠癌细胞系中进行。这些筛选确定了 CDK 抑制剂药物类别，是六个结直肠癌系中最有效的细胞毒性化合物。在这一类中，CDK1、2 和 9 的联合靶向是最有效的，IC50 范围为 110 nmol/L 至 1.2 μmol/L。在 CDK2 抑制剂 (CVT-313) 存在下敲除 CDK9 表明 CDK9 敲除与 CDK2 抑制协同作用。从机制上讲，双重 CDK2/9 抑制诱导了显着的 G2-M 停滞和后期灾难。体内联合抑制 CDK2/9 协同减少 PDX 肿瘤生长。我们的精准医疗管道提供了一个强大的筛选和验证平台，以识别有前景的新癌症疗法。该平台在结直肠癌中的应用确定了 CDK2/9 双重抑制作为治疗结直肠癌的新型组合疗法。CDK2/9 双重抑制诱导了显着的 G2-M 停滞和后期灾难。体内联合抑制 CDK2/9 协同减少 PDX 肿瘤生长。我们的精准医学管道提供了一个强大的筛选和验证平台，以识别有前景的新癌症疗法。该平台在结直肠癌中的应用确定了 CDK2/9 双重抑制作为治疗结直肠癌的新型组合疗法。CDK2/9 双重抑制诱导了显着的 G2-M 停滞和后期灾难。体内联合抑制 CDK2/9 协同减少 PDX 肿瘤生长。我们的精准医疗管道提供了一个强大的筛选和验证平台，以识别有前景的新癌症疗法。该平台在结直肠癌中的应用确定了 CDK2/9 双重抑制作为治疗结直肠癌的新型组合疗法。