Exploiting MCL1 Dependency with Combination MEK + MCL1 Inhibitors Leads to Induction of Apoptosis and Tumor Regression in KRAS-Mutant Non–Small Cell Lung Cancer

Abstract

BH3 mimetic drugs, which inhibit pro-survival BCL-2 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 MCL-1 inhibitors, we demonstrate that concurrent MEK + MCL-1 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 MCL-1 or BCL-XL was determined by the differential binding of pro-apoptotic BCL-2 proteins to MCL-1 or BCL-XL, respectively. The efficacy of dual MEK + MCL-1 blockade was augmented by prior transient exposure to BCL-XL inhibitors, which promotes the binding of pro-apoptotic BCL-2 proteins to MCL-1. This suggests a novel strategy for integrating BH3 mimetics that target different BCL-2 family proteins for KRAS mutant NSCLC.

BH3-Mimetic Drugs: Blazing the Trail for New Cancer Medicines

“…Kinase inhibition increases expression of pro-apoptotic BH3-only proteins, such as BIM and PUMA, thereby inhibiting pro-survival BCL-2 proteins that are not targeted by the BH3-mimetics (Cragg et al, 2007(Cragg et al, , 2008Rohrbeck et al, 2016). Accordingly, combinations of MCL-1 inhibitors, such as S63845 and AMG 176 (and the related compound AM 8621), with inhibitors of EGFR, MEK, or B-RAF were shown to efficiently diminish the in vitro and even the in vivo growth of cell lines derived from NSCLC (Kotschy et al, 2016;Leverson et al, 2015b;Nangia et al, 2018;Song et al, 2005;Zhang et al, 2011), lung squamous cell carcinoma (Weeden et al, 2018), hepatocarcinoma, or glioblastoma (Karpel-Massler et al, 2017). Of note, $85% of ER-positive breast cancers express high levels of BCL-2 (Dawson et al, 2010) and, accordingly, venetoclax and navitoclax synergized with tamoxifen in inhibiting the growth of patient-derived xenografts in mice (Vaillant et al, 2013).…”

“…Further structure-based drug discovery exploiting the subtle differences between the binding interfaces of BCL-2 versus BCL-XL led to the development of the BCL-2-selective in-related compound, S64315/MIK665, is now being co-developed in the clinic with Novartis. Concomitantly, Amgen and Astra-Zeneca have disclosed their respective MCL-1 inhibitor programs and have initiated clinical trials with AMG 176 Nangia et al, 2018;Ramsey et al, 2018) and AZD5991 (Hird et al, 2017), respectively.…”

STING-dependent paracriny shapes apoptotic priming of breast tumors in response to anti-mitotic treatment

“…Venetoclax (selectively targeting BCL-2) was the first BH3 mimetic approved for treating BCL-2-dependent chronic lymphocytic leukemia 12 . Dual BCL-2/BCL-xL inhibitors (ABT-737 or ABT-263/Navitoclax) or selective inhibitor of BCL-xL (WEHI-539) are also available and some have already been shown to potentiate the effects of chemotherapy in breast cancers in preclinical studies [13][14][15] .…”

Unleashing Blocked Apoptosis in Cancer Cells: New MCL1 Inhibitors Find Their Groove

“…Trametinib prevented phosphorylationinduced degradation of BIM, thereby increasing the amount of BIM bound to BCL-xL that can be displaced by navitoclax ( Fig 1B-ii). In the current article, they used AM-8621 to demonstrate that an equivalent inhibitor-sensitive loading of MCL1 occurred as it also synergized with trametinib-thus indicating joint addiction to BCL-xL and MCL1 in these tumors (10). In NSCLC lines and xenografts, therapy with trametinib and either AM-8621 or navitoclax caused tumor regression that was significant but incomplete.…”