Kato Shumei, Porter Robert, Okamura Ryosuke, Lee Suzanna, Zelichov Ori, Tarcic Gabi, Vidne Michael, Kurzrock Razelle
Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, La Jolla, CA, USA.
NovellusDX, Jerusalem, Israel.
Eur J Cancer. 2021 May;149:184-192. doi: 10.1016/j.ejca.2021.01.055. Epub 2021 Apr 14.
RAS variant-related functional impact on the mitogen-activated protein kinase (MAPK) pathway, and correlation between MAPK activation and MAPK/ERK kinase (MEK) inhibitor responsiveness, is not established.
Of 1,693 tumours sequenced, 576 harboured a RAS alteration; 62 patients received an MEK inhibitor (MEKi) and had RAS mutations that were functionally characterised. We report that RAS mutants have variable levels of MAPK activity, as measured by a functional cell-based assay that quantified MAPK pathway activation after transfection with a variety of RAS mutations.
Patients with tumours harbouring RAS alterations with high versus low MAPK activity who were treated with an MEKi showed significantly longer median progression-free survival (PFS) (5.0 vs. 2.3 months; p = 0.0034) and overall survival (20.0 vs. 5.0 months; p = 0.0146) and a trend towards higher rates of clinical benefit (stable disease ≥6 months or partial/complete remission) (38% versus 15%; p = 0.095) (p-values as per univariate analysis). PFS remained statistically significant after the multivariate analysis (p = 0.003).
These results support a correlation between RAS-mutant cancers with greater MAPK signalling and PFS after MEKi treatment.
RAS变异对丝裂原活化蛋白激酶（MAPK）通路的功能影响以及MAPK激活与MAPK/细胞外信号调节激酶（MEK）抑制剂反应性之间的相关性尚未明确。
在1693例测序肿瘤中，576例存在RAS改变；62例患者接受了MEK抑制剂（MEKi）治疗，并对其具有功能特征的RAS突变进行了研究。我们报告，通过基于细胞的功能检测来测量RAS突变体的MAPK活性水平各异，该检测在转染多种RAS突变后对MAPK通路激活进行了量化。
接受MEKi治疗的RAS改变肿瘤患者中，MAPK活性高与低的患者相比，中位无进展生存期（PFS）显著更长（5.0个月对2.3个月；p = 0.0034），总生存期也显著更长（20.0个月对5.0个月；p = 0.0146），并且临床获益率（疾病稳定≥6个月或部分/完全缓解）有升高趋势（38%对15%；p = 0.095）（单因素分析p值）。多因素分析后PFS仍具有统计学意义（p = 0.003）。
这些结果支持RAS突变型癌症中较高的MAPK信号传导与MEKi治疗后的PFS之间存在相关性。
