CDK4/6 Inhibitor, Palbociclib, overcomes Venetoclax resistance mechanisms and outperforms single agents in Acute Myeloid Leukemia [CRISPR Screen]

Venetoclax (ven) combined with the hypomethylating agent azacytidine (aza) is a widely used therapy for Acute Myeloid Leukemia (AML), however, most patients develop resistance. A genome-wide CRISPR screen showed that loss of genes involved in translation conferred sensitivity to ven but not ven+palbo. Accordingly, we show that increased translation occurs after AML cells are challenged with ven, and ven+palbo blocks this increase. We also found that loss of BAX, which leads to ven resistance, was overcome by combination with CDK4/6 inhibitors. Conversely, loss of RB1, a known mechanism of resistance to CDK4/6 inhibitors, was mitigated by ven+palbo. This work suggests that the combination of ven+palbo is a potential novel therapy for AML for potential subpopulations that may benefit the most from this treatment, as well as targeting translation as a means to overcome ven resistance. Overall design: Using a genome-wide CRISPR screen on OCI-AML2 cells, we performed comparisons of sgRNA read counts between DMSO and venetoclax, palbociclib as well as their combination at Day 0 and 21. Genes that were significantly depleted (enriched) relative to DMSO controls were deemed candidates for enhancing drug sensitivity (resistance).