What dictates cellular responses to chemotherapies that target DNA repair pathways?
DNA repair pathways have been the target of multiple FDA-approved and experimental chemotherapies. The success of these therapies depends on the increased reliance of rapidly proliferating cancer cells on DNA replication and repair pathways. However, holistic responses to chemotherapies are an amalgamation of multiple cellular pathways and physiological settings. We are interested in decoding the molecular determinants that dictate chemotherapeutic response with the broad goal of tailoring treatment regimens and uncovering biological circuits that ensure genomic stability.
How cancer cells deal with roadblocks to replication?
Oncogenic transformations are often associated with genomic alterations that can challenge DNA replication. Owing to the essentiality of genome duplication for cell survival, cancers evolve pathways to surmount obstacles to replication. Intriguingly, depending on the cellular context, these obstacles come in “different flavors”. By designing genetically defined systems to mimic different replication stress responses, the lab aims to define genome rescue mechanisms that are common and unique across cancer types.
What are the endogenous DNA lesions in BRCA-mutant cancer cells?
Cancers are characterized by aberrations in chromosomal numbers and characteristic DNA lesions, including damaged replication forks, single-strand breaks and double-strand breaks. The endogenous sources of these abnormalities remain unclear. In theory, any unresolved chemical modification in the nucleotide backbone of DNA can be the initiating molecular event for genomic instability when HR fails. We are interested in examining the unexplored link between nucleotide abnormalities and oncogenic transformations in HR-deficient cancers. These findings can be the key to understanding the innate molecular events that led to malignancy, and perhaps also reveal the basis for the known predilection of HR deficiency to result in cancers only in specific tissue types. This information can result in the discovery of biomarkers that can aid in the early detection of cancer. It may also be used to avoid exogenous exposures that lead to the genesis of such precipitating lesions.