Universitą degli studi di Pavia
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Bertoletti research activity
Role of double-strand breaks repair mechanisms (non-homologous end-joining, NHEJ) in tumor cells.
Targeted molecular therapy is at the forefront of current anticancer treatment development. Such a strategy, when combined with the selection of a precise molecular target as a function of the tumor genetic background, allows to fully exploit the synthetic lethality effect, whereby the intrinsic lack of certain cellular function, still compatible with cell survival, becomes lethal when combined with the suppression of a compensatory pathway. A recent example are the inhibtors of the DNA repair enzyme PARP-1, when used in the context of cells compromised in the homologous recombination (HR) repair of DNA breaks, such as in BRCA-1 and BRCA-2 deficient tumors. A signifcant fraction of treated patients, however, resulted resistant to PARP-1 inhibitors in phase 3 clinical trials. The most likely mechanism of such a resiliance was the activation of alternative repair pathways, such as NHEJ. However, knocking down NHEJ genes expression, resulted in even higher resiliance towards PARP-1 inhibitors, indicating the presence of yet more efficient (and probably more mutagenic) compensatory pathways. Our laboratory has gained evidence that the human DNA polymerase lambda might be involved in such pathways. This project aims to investigate the role of DNA polymerase lambda in PARP-1 inhibitor resistance, using model cells lines deficient in BRCA-1 and BRCA-2. Through selective knockdown of DNA polymerase lambda and other related genes expression, we want to clarify the molecular pathways involved in these alternative repair mechanisms
Targeted molecular therapy is at the forefront of current anticancer treatment development. Such a strategy, when combined with the selection of a precise molecular target as a function of the tumor genetic background, allows to fully exploit the synthetic lethality effect, whereby the intrinsic lack of certain cellular function, still compatible with cell survival, becomes lethal when combined with the suppression of a compensatory pathway. A recent example are the inhibtors of the DNA repair enzyme PARP-1, when used in the context of cells compromised in the homologous recombination (HR) repair of DNA breaks, such as in BRCA-1 and BRCA-2 deficient tumors. A signifcant fraction of treated patients, however, resulted resistant to PARP-1 inhibitors in phase 3 clinical trials. The most likely mechanism of such a resiliance was the activation of alternative repair pathways, such as NHEJ. However, knocking down NHEJ genes expression, resulted in even higher resiliance towards PARP-1 inhibitors, indicating the presence of yet more efficient (and probably more mutagenic) compensatory pathways. Our laboratory has gained evidence that the human DNA polymerase lambda might be involved in such pathways. This project aims to investigate the role of DNA polymerase lambda in PARP-1 inhibitor resistance, using model cells lines deficient in BRCA-1 and BRCA-2. Through selective knockdown of DNA polymerase lambda and other related genes expression, we want to clarify the molecular pathways involved in these alternative repair mechanisms
