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  • Title: Exploiting MCL1 Dependency with Combination MEK + MCL1 Inhibitors Leads to Induction of Apoptosis and Tumor Regression in KRAS-Mutant Non-Small Cell Lung Cancer.
    Author: Nangia V, Siddiqui FM, Caenepeel S, Timonina D, Bilton SJ, Phan N, Gomez-Caraballo M, Archibald HL, Li C, Fraser C, Rigas D, Vajda K, Ferris LA, Lanuti M, Wright CD, Raskin KA, Cahill DP, Shin JH, Keyes C, Sequist LV, Piotrowska Z, Farago AF, Azzoli CG, Gainor JF, Sarosiek KA, Brown SP, Coxon A, Benes CH, Hughes PE, Hata AN.
    Journal: Cancer Discov; 2018 Dec; 8(12):1598-1613. PubMed ID: 30254092.
    Abstract:
    BH3 mimetic drugs, which inhibit prosurvival BCL2 family proteins, have limited single-agent activity in solid tumor models. The potential of BH3 mimetics for these cancers may depend on their ability to potentiate the apoptotic response to chemotherapy and targeted therapies. Using a novel class of potent and selective MCL1 inhibitors, we demonstrate that concurrent MEK + MCL1 inhibition induces apoptosis and tumor regression in KRAS-mutant non-small cell lung cancer (NSCLC) models, which respond poorly to MEK inhibition alone. Susceptibility to BH3 mimetics that target either MCL1 or BCL-xL was determined by the differential binding of proapoptotic BCL2 proteins to MCL1 or BCL-xL, respectively. The efficacy of dual MEK + MCL1 blockade was augmented by prior transient exposure to BCL-xL inhibitors, which promotes the binding of proapoptotic BCL2 proteins to MCL1. This suggests a novel strategy for integrating BH3 mimetics that target different BCL2 family proteins for KRAS-mutant NSCLC. SIGNIFICANCE: Defining the molecular basis for MCL1 versus BCL-xL dependency will be essential for effective prioritization of BH3 mimetic combination therapies in the clinic. We discover a novel strategy for integrating BCL-xL and MCL1 inhibitors to drive and subsequently exploit apoptotic dependencies of KRAS-mutant NSCLCs treated with MEK inhibitors.See related commentary by Leber et al., p. 1511.This article is highlighted in the In This Issue feature, p. 1494.
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