Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Antitumor T-cell Immunity
In: Cancer Discovery, Jg. 11 (2021-03-01), S. 714-735
Online
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Zugriff:
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, BRAFnon-V600, and BRAFV600 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 BRAFV600MUT 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
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Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Antitumor T-cell Immunity
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Autor/in / Beteiligte Person: | Hong, Aayoung ; Yang, Zhentao ; Vega-Crespo, Agustin ; Lo, Roger S. ; Donahue, Timothy R. ; Scumpia, Philip O. ; Shackelford, David B. ; Moriceau, Gatien ; Lomeli, Shirley H. ; Tackett, Alan J. ; Lee, Jordan J. ; Holmen, Sheri L. ; Lo, Skylar J. ; Ribas, Antoni ; Randolph, Christopher E. ; Garcia, Alejandro J. ; Zoete, Vincent ; Liu, Sixue ; Dubinett, Steven M. ; Sun, Lu ; Byrum, Stephanie D. ; Hugo, Willy ; Michielin, Olivier ; Piva, Marco ; Wang, Yan |
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Zeitschrift: | Cancer Discovery, Jg. 11 (2021-03-01), S. 714-735 |
Veröffentlichung: | American Association for Cancer Research (AACR), 2021 |
Medientyp: | unknown |
ISSN: | 2159-8290 (print) ; 2159-8274 (print) |
DOI: | 10.1158/2159-8290.cd-20-0873 |
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