LB999 Basal levels of MCL1 and its binding partners contribute to a higher sensitivity to MCL1 inhibitors in uveal vs cutaneous melanomas

The two subtypes of melanomas, uveal (UM) and cutaneous (CM), originate from melanocyte transformation, but differ in their genetic etiology signaling pathways. MCL1 BCL2, the anti-apoptotic members BCL2 family, induce anti-cancer treatment resistance. Here, we evaluate basal levels role inducing response to inhibitor (MCL1i) CM UM. We used vitro assays (viability, immunoblot shRNA), bioinformatics analyses TCGA database. UM cell lines have higher lower protein expressions compared CM. Mechanistic studies using shRNAs suggest knockdown (KD) led ∼30% reduction viability sensitized them MCL1i (p<0.001); however, KD did not significantly alter or sensitivity MCL1i. significant effect either Thus, may play a larger UM, further understand, looked at binding partners MCL1: BOK, BAK, BIM, NOXA PUMA. had BAK PUMA BIM partial protection against induced death multiple (p<0.05), while effects were variable. Further with BOK are progress. Results low expression high pro-apoptotic family that bind contributes inhibitors. To determine clinical relevance, analyzed gene database 34 cancer types. much MCL1, (p<0.001). In addition, highest level our consistent samples. Overall, data indicates its differences CM’s MCL1i, is good candidate for