Bristol Myers-Squibb, Cambridge, Massachusetts.
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Clin Cancer Res. 2021 Apr 1;27(7):2061-2073. doi: 10.1158/1078-0432.CCR-20-2563. Epub 2020 Dec 22.
Targeting RAF for antitumor therapy in RAS-mutant tumors holds promise. Herein, we describe in detail novel properties of the type II RAF inhibitor, LXH254.
LXH254 was profiled in biochemical, , and assays, including examining the activities of the drug in a large panel of cancer-derived cell lines and a comprehensive set of models. In addition, activity of LXH254 was assessed in cells where different sets of RAF paralogs were ablated, or that expressed kinase-impaired and dimer-deficient variants of ARAF.
We describe an unexpected paralog selectivity of LXH254, which is able to potently inhibit BRAF and CRAF, but has less activity against ARAF. LXH254 was active in models harboring BRAF alterations, including atypical BRAF alterations coexpressed with mutant K/NRAS, and mutants, but had only modest activity in mutants. In RAS-mutant lines, loss of ARAF, but not BRAF or CRAF, sensitized cells to LXH254. ARAF-mediated resistance to LXH254 required both kinase function and dimerization. Higher concentrations of LXH254 were required to inhibit signaling in RAS-mutant cells expressing only ARAF relative to BRAF or CRAF. Moreover, specifically in cells expressing only ARAF, LXH254 caused paradoxical activation of MAPK signaling in a manner similar to dabrafenib. Finally, , LXH254 drove complete regressions of isogenic variants of RAS-mutant cells lacking ARAF expression, while parental lines were only modestly sensitive.
LXH254 is a novel RAF inhibitor, which is able to inhibit dimerized BRAF and CRAF, as well as monomeric BRAF, while largely sparing ARAF.
针对 RAS 突变肿瘤中的 RAF 进行抗肿瘤治疗具有一定的前景。在此，我们详细描述了 II 型 RAF 抑制剂 LXH254 的新特性。
在生化、细胞和体内测定中对 LXH254 进行了分析，包括检查该药物在大量癌症衍生细胞系和全面的模型中的活性。此外，还评估了在不同 RAF 同源物被剔除的细胞中或表达激酶失活和二聚体缺陷变异型 ARAF 的细胞中 LXH254 的活性。
我们描述了 LXH254 的一种意想不到的平行物选择性，它能够强烈抑制 BRAF 和 CRAF，但对 ARAF 的活性较低。LXH254 在携带 BRAF 改变的模型中具有活性，包括与突变 K/NRAS 共表达的非典型 BRAF 改变，以及 V600E 突变，但在 V600K 突变中活性较低。在 RAS 突变系中，丧失 ARAF 而非 BRAF 或 CRAF 可使细胞对 LXH254 敏感。ARAF 介导的对 LXH254 的耐药性需要激酶功能和二聚化。与 BRAF 或 CRAF 相比，仅表达 ARAF 的 RAS 突变细胞中需要更高浓度的 LXH254 来抑制信号。此外，特别是在仅表达 ARAF 的细胞中，与 dabrafenib 相似，LXH254 导致 MAPK 信号的反常激活。最后，在体内，LXH254 驱动缺乏 ARAF 表达的 RAS 突变细胞的同系物完全消退，而亲本细胞仅有适度的敏感性。
LXH254 是一种新型的 RAF 抑制剂，能够抑制二聚化的 BRAF 和 CRAF，以及单体化的 BRAF，而在很大程度上保留 ARAF。
