Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Asana BioSciences, Lawrenceville, NJ, USA.
Cell Rep Med. 2021 Jul 21;2(7):100350. doi: 10.1016/j.xcrm.2021.100350. eCollection 2021 Jul 20.
Inhibition of the extracellular signal-regulated kinases ERK1 and ERK2 (ERK1/2) offers a promising therapeutic strategy in cancers harboring activated RAS/RAF/MEK/ERK signaling pathways. Here, we describe an orally bioavailable and selective ERK1/2 inhibitor, ASN007, currently in clinical development for the treatment of cancer. In preclinical studies, ASN007 shows strong antiproliferative activity in tumors harboring mutations in BRAF and RAS (KRAS, NRAS, and HRAS). ASN007 demonstrates activity in a BRAF mutant melanoma tumor model that is resistant to BRAF and MEK inhibitors. The PI3K inhibitor copanlisib enhances the antiproliferative activity of ASN007 both and due to dual inhibition of RAS/MAPK and PI3K survival pathways. Our data provide a rationale for evaluating ASN007 in RAS/RAF-driven tumors as well as a mechanistic basis for combining ASN007 with PI3K inhibitors.
抑制细胞外信号调节激酶 ERK1 和 ERK2（ERK1/2）为具有激活 RAS/RAF/MEK/ERK 信号通路的癌症提供了一种有前途的治疗策略。在这里，我们描述了一种正在临床开发用于癌症治疗的口服生物利用度和选择性 ERK1/2 抑制剂 ASN007。在临床前研究中，ASN007 在携带 BRAF 和 RAS（KRAS、NRAS 和 HRAS）突变的肿瘤中显示出强烈的抗增殖活性。ASN007 在对 BRAF 和 MEK 抑制剂耐药的 BRAF 突变黑色素瘤肿瘤模型中具有活性。PI3K 抑制剂 copanlisib 由于双重抑制 RAS/MAPK 和 PI3K 存活途径，增强了 ASN007 的抗增殖活性。我们的数据为评估 ASN007 在 RAS/RAF 驱动的肿瘤中的作用提供了依据，并为 ASN007 与 PI3K 抑制剂联合使用提供了机制基础。
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