Focus on Drug Resistance and Aberrant Growth of Cancer Cells
A key barrier in developing precision medicine for cancers is lack of a comprehensive understanding at the molecular level of what promotes drug resistance and aberrant growth of cancer cells compared to the normal cells. For example, inhibition of a critical DNA repair factor, poly(ADP-ribose) polymerase-1 (PARP1), is a promising strategy for targeting cancers with defective DNA double-strand break (DSB) repair such as BRCA1 and BRCA2 mutation-associated breast cancers. Deficiencies in BRCA1 and BRCA2 genes can compromise homologous recombination (HR) to repair double-strand breaks created by the loss of PARP1 activity, conferring cell death by synthetic lethality.
However, the rarity of breast tumors with BRCA deficiency currently restricts the therapeutic utility of PARP inhibitor (PARPi) monotherapy and several potential molecular mechanisms of resistance for PARP1i in BRCA-deficient breast cancers have been reported. One striking paradox, though, is that approximately 24 percent of high-grade triple negative breast cancers (TNBC) without a BRCA mutation responded positively to PARP1i in Phase II clinical trials. These confounding observations clearly posit a search for suitable predictive biomarkers (i.e., markers for resistance and sensitivity), novel therapeutic targets and innovative strategies that can potentiate the DNA damaging effects of PARP1i beyond BRCA deficiencies.
The Motea lab is investigating the mechanistic basis for synthetic lethality between loss of both PARP activity and specific transcription termination factors in BRCA-proficient cancers. Specifically, this lab team is trying to understand how cancer cells with aberrant alterations in these factors can induce formation of genotoxic R-loops (three-stranded nucleic acid structures that contain RNA:DNA hybrid and a displaced single-stranded DNA) and genomic instability at the molecular level using proteomics, genomics, bioinformatics, molecular biology, chemical biology, and pharmacological approaches.
Overall, understanding the mechanisms underlying R-loop-mediated genomic instability may provide key insights into (1) unannotated biological pathways; (2) the pathogenesis of many diseases and syndromes including cancer and neurological disorders; and (3) identification of novel targets and innovative strategies to leverage the formation, resolution, and/or processing of R-loops for precision medicine.