Original ArticleBIK is involved in BRAF/MEK inhibitor induced apoptosis in melanoma cell lines

- BIK expression correlates with apoptosis upon BRAF/MEK inhibition in melanoma cells.
- BRAF/MEK inhibition of BRAF-mutant melanoma cells selects for BIKlow cells.
- Ectopic BIK expression increases apoptotic response to MAPK pathway inhibition.
- BIK knockdown/knockout reduces apoptotic response to MAPK pathway inhibition.
- HDAC inhibition leads to elevated BIK levels and sensitizes to BRAF/MEK inhibition.

In patients with BRAF-mutated melanoma specific inhibitors of BRAFV600E and MEK1/2 frequently induce initial tumor reduction, frequently followed by relapse. As demonstrated previously, BRAFV600E-inhibition induces apoptosis only in a fraction of treated cells, while the remaining arrest and survive providing a source or a niche for relapse. To identify factors contributing to the differential initial response towards BRAF/MEK inhibition, we established M14 melanoma cell line-derived single cell clones responding to treatment with BRAF inhibitor vemurafenib and MEK inhibitor trametinib predominantly with either cell cycle arrest (CCA-cells) or apoptosis (A-cells). Screening for differentially expressed apoptosis-related genes revealed loss of BCL2-Interacting Killer (BIK) mRNA in CCA-cells. Importantly, ectopic expression of BIK in CCA-cells resulted in increased apoptosis rates following vemurafenib/trametinib treatment, while knockdown/knockout of BIK in A-cells attenuated the apoptotic response. Furthermore, we demonstrate reversible epigenetic silencing of BIK mRNA expression in CCA-cells. Importantly, HDAC inhibitor treatment associated with re-expression of BIK augmented sensitivity of CCA-cells towards vemurafenib/trametinib treatment both in vitro and in vivo. In conclusion, our results suggest that BIK can be a critical mediator of melanoma cell fate determination in response to MAPK pathway inhibition.