Here, we selectively target pancreatic ductal adenocarcinoma (PDAC) cells harboring a hemizygous gene essential for cell growth. MYB binding protein 1A (MYBBP1A), encoding a chromatin-bound protein, is hemizygous in most of the PDAC due to a chromosome 17p deletion that also spans TP53 We find that hemizygous MYBBP1A loss in isogenic PDAC cells promotes tumorigenesis but, paradoxically, homozygous MYBBP1A loss is associated with impaired cell growth and decreased tumorigenesis. Poly-adenosine 5'-diphosphate-ribose polymerase 1 (PARP1) interacts with MYBBP1A and displaces it from chromatin. Small molecules, such as olaparib, that trap PARP1 to chromatin are able to evict the minimal pool of chromatin-bound MYBBP1A protein in MYBBP1A hemizygous cells and impair cell growth, greater than its impact on wild-type cells. Our findings reveal how a cell essential gene with one allele lost in cancer cells can be preferentially susceptible to a specific molecular therapy, when compared to wild-type cells.
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