Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Antitumor T-cell Immunity

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, 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

Drug combination screening as a translational approach toward an improved drug therapy for chordoma

“…We conducted this screen in UM-Chor1, which is a clival chordoma cell line that has been proven to be sensitive to EGFR i s [9][10][11]. The analysis of whole genome sequencing data revealed that this cell line carries a PTEN L139* nonsense mutation [12], which has also been described in conventional glioblastoma, endometrial and breast cancers [30]. Tarpey et al did not detect any recurrent genetic drivers in their genetic analyses of 104 sporadic chordomas, but alterations in phosphoinositide-3 kinase signalling (including occasional mutations in PIK3CA and PTEN) were amongst the more common genetic events reported [12].…”

Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy

“…Trametinib dose level for each tumor model was chosen based on the minimal dose required to elicit tumor stabilization or regression early on-treatment and near complete p-ERK suppression on d3 (Figure S2A). We used six murine syngeneic tumor models: (1) Braf V600E melanoma with high mutational burden (HMB) (YUMM1.7ER; Figure 2B) (Wang et al, 2017), (2) Nras Q61R melanoma (NIL; Figure 2C) (Hong et al, 2018), (3) Nras Q61R melanoma with high mutational burden (NILER1-4; Figure 2D) (Hong et al, 2021), (4) Nf1 À/À melanoma (mSK-Mel254; Figure 2E), (5) Kras G12C colorectal carcinoma (CT26; Figure 2F), and (6) Kras G12C pancreatic adenocarcinoma (KPC; Figure 2G).…”

“…This sequential-combinatorial fusion may avoid the development of cross-resistance, raise the threshold for resistance evolution by stacking multiple therapeutic mechanisms of action, and permit one mode of therapy to prime responsiveness to the other, thereby creating synergy. Importantly, previous studies have implicated a role of antitumor immunity in prolonging, clinically and preclinically, the durability of MAPKi responses (Hong et al, 2021;Hugo et al, 2015).…”

Targeting BRAF and RAS in Colorectal Cancer

“…Another report showed in preclinical models that combining a BRAF dimer inhibitor with an MEK inhibitor induced a dramatic therapeutic effect and overcame acquired resistance among cancers with KRAS, NRAS, NF1, BRAF non-V600E, and BRAF V600E mutations. Such therapies isolate MEK in RAF complexes, then reduce MEK/MEK dimerization, and uncouple MEK from ERK in acquired resistant tumor subpopulations [ 76 ] ( Table 2 ).…”