Sieber, O. | Search bioRxiv

bioRxiv2024

SRP19 and the protein secretion machinery is a targetable vulnerability in cancers with APC loss

Adenomatous Polyposis Coli (APC) is a tumour suppressor that is frequently lost in colorectal and other cancers. A common mechanism for APC loss includes heterozygous APC deletion. Here, we show that SRP19, is located near APC and is often co-deleted in these tumours. Heterozygous APC/SRP19 loss leads to lower levels of SRP19 mRNA and protein. Consequently, cells with APC/SRP19 loss are vulnerable to partial suppression of SRP19. We show that SRP19 loss is a unique vulnerability since SRP19 is rate limiting for the formation of the Signal Recognition Particle (SRP), a complex that mediates translocation of proteins to the ER. Consistent with these observations, partial SRP19 knock-down or low dose Arsenic Trioxide treatment induces ER stress and inhibits proliferation in APC/SRP19 loss cancers. Our work identifies a new strategy to treat cancers with APC/SRP19 heterozygous deletions and provides a framework for identifying vulnerabilities associated with loss of a tumour suppressor.

cancer biology↗

bioRxiv2021

Dual MAPK and HDAC inhibition rewires the apoptotic rheostat to trigger colorectal cancer cell death

The EGFR/RAS/MEK/ERK signalling pathway (ERK/MAPK) is hyper-activated in most colorectal cancers (CRCs). A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in CRC cells. Nevertheless, these drugs do induce expression of pro-apoptotic factors, suggesting they may prime CRC cells to undergo apoptosis. As histone deacetylase inhibitors (HDACi) induce expression of multiple pro-apoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger CRC cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in CRC cell lines and patient-derived tumour organoids in vitro, and attenuated Apc-initiated adenoma formation in vivo. Mechanistically this effect was mediated through induction of the BH3-only pro-apoptotic proteins BIM and BMF. Importantly, we demonstrate that this treatment paradigm can be tailored to specific MAPK genotypes in CRCs, by combining HDACi with EGFR, KRASG12C or BRAFV600 inhibitors in KRAS/BRAFWT; KRASG12C, BRAFV600E CRC cell lines respectively. These findings identify a novel ERK/MAPK genotype-targeted treatment paradigm for colorectal cancer.

cancer biology↗