Acute MCL1 Loss via Homoharringtonine-Mediated Translational Inhibition Enables Potent Apoptotic Synergy with BCLXL Blockade.

Abstract

Antiapoptotic buffering in solid tumors is generally mediated by both BCLXL and MCL1, so that BH3 mimetic drugs targeting only one have limited efficacy. To identify agents that may sensitize tumors to BH3 mimetics targeting BCLXL, we screened prostate cancer cells against a panel of mitochondria-targeted drugs in combination with navitoclax, a BH3 mimetic targeting BCL2 and BCLXL. Homoharringtonine (HHT) in combination with navitoclax and as a single agent emerged as a potent inducer of apoptosis. HHT has been identified as an inhibitor of protein translation, and proteomic analysis showed broad suppression of translation-related pathways, while immunoblotting demonstrated rapid decreases in short-lived proteins, including MCL1. HHT dose response and time course studies showed marked declines in MCL1 within 2 hours that were associated with apoptosis in response to BCLXL inhibition with navitoclax or A1331852. Further cell viability assays showed synergy between HHT and BCLXL inhibitors in multiple prostate, lung, and colorectal cancer cell lines. HHT monotherapy in vivo caused tumor regression in two prostate cancer xenograft models. Analysis of tumor tissue taken at 4 hours after dosing showed decreases in MCL1 and MYC, indicating that HHT levels obtainable in vivo are adequate to deplete short-lived proteins and potentially sensitize to BH3 mimetics targeting BCLXL. These findings support further exploration of HHT as a single agent in solid tumors and establish a rationale for investigating safer, tumor-selective approaches to combine HHT-mediated translational inhibition with BCLXL targeting.