Investigating PARP inhibition in colorectal cancer cell lines and combinatorial approaches to improve sensitivity

Colorectal cancer (CRC) still ranks as one of the most common cancers and a leading cause of cancer-related death worldwide and in Qatar, despite significant advances in surveillance and treatment. Moreover, 5-year survival rates are particularly dismal in metastatic cases due to limited therapeutic options and development of resistance. Disease heterogeneity presents an added layer of treatment complexity, thus requiring patient stratification and personalized therapy. The DNA damage response (DDR) pathway is central to maintaining genomic fidelity during cell division, and mutations in DDR-associated genes increase susceptibility to cancer development. DDR-related therapy, whereby failed DNA repair mechanisms are further exacerbated, has been extensively investigated and implemented in certain cancer types, including breast and ovarian cancers with BRCA1/2 mutations, however this treatment modality is still being explored for CRCs. About 20% of CRCs have mutations in DDR-associated genes, indicating potential sensitivity to DDR therapy. However, the limited clinical trials investigating PARP inhibitors- a type of DDR therapy, in CRC have been disappointing, primarily due to poor patient stratification, thus highlighting the pressing need to understand the mechanistic activity of PARP inhibition (PARPi) in this cancer, identify biomarkers of treatment response and design mechanistic combination therapies for improved treatment response. The proposed project aims at increasing the current understanding of PARPi mechanistic sensitivity in multiple CRC cellular models stratified by the status of microsatellite stability and p53 function- both of which have implications in PARPi sensitivity. Specifically, the project will implement multi-pronged strategies, including assessing proteomic dysregulations (mass spectrometry and OLINK analysis), cellular energetics and cell cycle fidelity, to investigate the effect of PARPi on CRC models. The ultimate goal is to improve PARPi sensitization in CRC and identify combinatorial targets for maximized therapeutic benefit.