Growth of pancreatic cancers with hemizygous chromosomal 17p loss of <i>MYBBP1A</i> can be preferentially targeted by PARP inhibitors.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33277249.
- Also identified by DOI 10.1126/sciadv.abc4517 and PMC identifier 7821900.
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Abstract
Here, we selectively target pancreatic ductal adenocarcinoma (PDAC) cells harboring a hemizygous gene essential for cell growth. <i>MYB binding protein 1A</i> (<i>MYBBP1A</i>), encoding a chromatin-bound protein, is hemizygous in most of the PDAC due to a chromosome 17p deletion that also spans <i>TP53</i> We find that hemizygous <i>MYBBP1A</i> loss in isogenic PDAC cells promotes tumorigenesis but, paradoxically, homozygous <i>MYBBP1A</i> 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 <i>MYBBP1A</i> 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.