Abstract
MCL1 has critical antiapoptotic functions and its levels are tightly regulated by ubiquitylation and degradation, but mechanisms that drive this degradation, particularly in solid tumors, remain to be established. We show here in prostate cancer cells that increased NOXA, mediated by kinase inhibitor activation of an integrated stress response, drives the degradation of MCL1, and identify the mitochondria-associated ubiquitin ligase MARCH5 as the primary mediator of this NOXA-dependent MCL1 degradation. Therapies that enhance MARCH5-mediated MCL1 degradation markedly enhance apoptosis in response to a BH3 mimetic agent targeting BCLXL, which may provide for a broadly effective therapy in solid tumors. Conversely, increased MCL1 in response to MARCH5 loss does not strongly sensitize to BH3 mimetic drugs targeting MCL1, but instead also sensitizes to BCLXL inhibition, revealing a codependence between MARCH5 and MCL1 that may also be exploited in tumors with MARCH5 genomic loss.
Highlights
Androgen deprivation therapy to suppress activity of the androgen receptor (AR) is the standard treatment for metastatic prostate cancer (PCa), but tumors invariably recur
We reported previously that treatment with several kinase inhibitors could markedly increase MCL1 degradation, and that this increase was not mediated by well-established MCL1 ubiquitin ligases including bTRCP, FBW7, HUWE1 (22)
In this study we initially found that erlotinib treatment rapidly increased expression of NOXA, and that the increased MCL1 degradation was NOXA-dependent
Summary
Androgen deprivation therapy to suppress activity of the androgen receptor (AR) is the standard treatment for metastatic prostate cancer (PCa), but tumors invariably recur (castration-resistant prostate cancer, CRPC). The anti-apoptotic BCL2 family proteins (including BCL2, BCLXL, and MCL1) act by neutralizing BAX and BAK, and by inhibiting the BH3-only pro-apoptotic proteins that can activate BAX/BAK (primarily BIM) (Montero and Letai, 2018). These interactions are mediated by the BH3 domain, and BH3-mimetic drugs can enhance apoptosis by mimicking the activity of BH3-only pro-apoptotic proteins and thereby antagonizing the anti-apoptotic BCL2 family proteins (Merino et al, 2018; Knight et al, 2019). A BCL2-specific agent that spares platelets (ABT-199, venetoclax) is active and is FDA approved for chronic lymphocytic leukemia (Pan et al, 2014; Roberts et al, 2016)
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