Using functional genetic screens to understand and overcome PARP inhibitor resistance

Paes Lobo Lopes Dias, M.

Heterozygous germ-line mutations in BRCA1 and BRCA2 predispose to several types of cancer. Owing to their roles in the error-free repair of DNA double-strand breaks (DSBs) via homologous recombination (HR), lack of BRCA1/2 in these tumors results in DNA damage defects that can be specifically targeted by the inhibition of Poly-(ADP-ribose) polymerase 1 (PARP1). PARP1 is a key sensor of DNA damage and its inhibition has been shown to be synthetically lethal with deficiencies in HR, resulting in the selective killing of BRCA1/2-deficient tumor cells, while sparing BRCA1/2-proficient non-tumor cells. The success of this approach has resulted in the approval of four PARP1 inhibitors (PARPi) for the treatment of ovarian, breast, prostate and pancreatic cancers. However, drug resistance poses a major obstacle as, despite initial responses, patients receiving PARPi often develop resistance to the treatment. Understanding the molecular mechanisms behind PARPi resistance is therefore...Show moreHeterozygous germ-line mutations in BRCA1 and BRCA2 predispose to several types of cancer. Owing to their roles in the error-free repair of DNA double-strand breaks (DSBs) via homologous recombination (HR), lack of BRCA1/2 in these tumors results in DNA damage defects that can be specifically targeted by the inhibition of Poly-(ADP-ribose) polymerase 1 (PARP1). PARP1 is a key sensor of DNA damage and its inhibition has been shown to be synthetically lethal with deficiencies in HR, resulting in the selective killing of BRCA1/2-deficient tumor cells, while sparing BRCA1/2-proficient non-tumor cells. The success of this approach has resulted in the approval of four PARP1 inhibitors (PARPi) for the treatment of ovarian, breast, prostate and pancreatic cancers. However, drug resistance poses a major obstacle as, despite initial responses, patients receiving PARPi often develop resistance to the treatment. Understanding the molecular mechanisms behind PARPi resistance is therefore crucial to identify key determinants of PARPi response and to find combination treatment strategies to overcome resistance to PARPi by preventing, delaying or targeting resistant clones. In this thesis, we expanded our insights into the molecular mechanisms underlying PARPi resistance by conducting functional genetic screens in PARPi-resistance cell lines.
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Using functional genetic screens to understand and overcome PARP inhibitor resistance