Multi-omics characterization of acquired Olaparib resistance in BRCA1 and BRCA2 mutant breast cancer cell lines

ABSTRACT: This is part 2 of the same project. Part 1 was just uploaded with the reference: 1-20250110-174238-3123982. Please merge if possible! Poly (ADP-ribose) polymerase inhibitors (PARPi) are widely used as targeted therapies against breast cancers with BRCA mutations. However, the development of resistance to PARPi poses a significant challenge for these therapies, warranting further need for mechanistic insight into PARPi resitance. Here, we generate and characterize Olaparib resistant (OR) clones of BRCA1/2 mutant breast cancer cell lines MDAMB436 and HCC1428 using a systems-level multi-omics approach, including transcriptome, proteome, phosphoproteome and ADP-ribosylation analysis. Our analyses revealed that resistance development was most strongly driven by protein changes, with modest effects on phosphorylation- and ADP-ribosylation-dependent signaling pathways. We found that BRCA1 expression was reestablished in all OR MDAMB436 clones, whereas PARP1 expression was decreased. In OR HCC1428 clones, BRCA2 function was not restored. However, we saw increased expression of Fanconi anemia group D2 (FANCD2), HPF1 and Nicotinamide phosphoribosyltransferase (NAMPT) in various OR clones, suggesting increased replication fork protection, changes in the ADPr pathway and adaptation of metabolic pathways as a resistance mechanism. Our findings provide valuable insights into the complex landscape of PARPi resistance, offering potential targets for further investigation and therapeutic intervention.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Holda Anagho-Mattanovich  

LAB HEAD: Michael L. Nielsen

PROVIDER: PXD060046 | Pride | 2025-08-25

REPOSITORIES: Pride