학술논문
Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Antitumor T-cell Immunity
Document Type
article
Author
Hong, Aayoung; Piva, Marco; Liu, Sixue; Hugo, Willy; Lomeli, Shirley H; Zoete, Vincent; Randolph, Christopher E; Yang, Zhentao; Wang, Yan; Lee, Jordan J; Lo, Skylar J; Sun, Lu; Vega-Crespo, Agustin; Garcia, Alejandro J; Shackelford, David B; Dubinett, Steven M; Scumpia, Philip O; Byrum, Stephanie D; Tackett, Alan J; Donahue, Timothy R; Michielin, Olivier; Holmen, Sheri L; Ribas, Antoni; Moriceau, Gatien; Lo, Roger S
Source
Cancer Discovery. 11(3)
Subject
Language
Abstract
MAPK targeting in cancer often fails due to MAPK reactivation. MEK inhibitor (MEKi) monotherapy provides limited clinical benefits but may serve as a foundation for combination therapies. Here, we showed that combining a type II RAF inhibitor (RAFi) with an allosteric MEKi durably prevents and overcomes acquired resistance among cancers with KRAS, NRAS, NF1, BRAF non-V600, and BRAF V600 mutations. Tumor cell-intrinsically, type II RAFi plus MEKi sequester MEK in RAF complexes, reduce MEK/MEK dimerization, and uncouple MEK from ERK in acquired-resistant tumor subpopulations. Immunologically, this combination expands memory and activated/exhausted CD8+ T cells, and durable tumor regression elicited by this combination requires CD8+ T cells, which can be reinvigorated by anti-PD-L1 therapy. Whereas MEKi reduces dominant intratumoral T-cell clones, type II RAFi cotreatment reverses this effect and promotes T-cell clonotypic expansion. These findings rationalize the clinical development of type II RAFi plus MEKi and their further combination with PD-1/L1-targeted therapy. SIGNIFICANCE: Type I RAFi + MEKi are indicated only in certain BRAF V600MUT cancers. In contrast, type II RAFi + MEKi are durably active against acquired MEKi resistance across broad cancer indications, which reveals exquisite MAPK addiction. Allosteric modulation of MAPK protein/protein interactions and temporal preservation of intratumoral CD8+ T cells are mechanisms that may be further exploited.This article is highlighted in the In This Issue feature, p. 521.