Biology subjects

Burke-Aguero, D. H.

Publications and source records attributed to Burke-Aguero, D. H..

3 recordsLinked to original sources

bioRxiv2025

DUSP11 is an intracellular innate immune checkpoint in lung adenocarcinoma

The discovery of immune checkpoints and the rapid growth of immuno-oncology (IO) have sparked tremendous efforts to utilize the immune system to treat a wide range of cancer types/subtypes. While the major focus of IO over the past decades has been to manipulate the adaptive immune system, recent attention has been given to manipulating the innate immune system to treat cancer and/or to enhance adaptive responses. In this work we detail the intracellular protein, Dual Specificity Phosphatase 11 (DUSP11), as an innate immune checkpoint (iIC) in Non-Small Cell Lung Cancer (NSCLC) adenocarcinoma (LUAD). Expression of this atypical phosphatase is correlated with patient survival for multiple cancer types, and we show here that its activity is important for the viability of lung cancer cells in vitro. Specifically, we demonstrate that DUSP11 knockdown in LUAD cells induces apoptosis and an innate immune response capable of activating other cells in vitro, and we provide evidence that these phenotypes are primarily mediated by the pattern recognition receptor, retinoic acid inducible gene I (RIG-I). Finally, we show that expression of DUSP11 is important for tumor engraftment and growth of human LUAD in mice. Overall, these data are the first to establish DUSP11 as an immunosuppressive, pro-neoplastic, and potentially targetable protein in LUAD. In addition, our data suggests that the anti-cancer mechanisms induced by diminishing the activity of DUSP11 are likely to be generalizable to other cancer types such as breast cancer, warranting future investigation and therapeutic development.

cancer biology↗

bioRxiv2024

Anti-EGFR aptamer exhibits direct anti-cancer effects in NSCLC cells harboring EGFR L858R mutations

Non-small cell lung cancer (NSCLC) adenocarcinoma (LUAD) is a leading cause of death worldwide. Activating mutations in the tyrosine kinase domain of the oncogene epidermal growth factor receptor (EGFR) are responsible for [~]10-50% of all LUAD cases. Although EGFR tyrosine kinase inhibitors (TKIs) have been effective in prolonging NSCLC patient survival and quality of life, acquired resistance mechanisms and disease progression are inevitable. Contemporary second- and third-line treatments, such as immunotherapy, remain ineffective for these patients, presenting a clear and unmet need for alternative or adjuvant therapeutics for the treatment of mutant EGFR positive NSCLC. Here we show that an anti-EGFR aptamer (EGFRapt) decreases viability of NSCLC cell lines harboring the L858R {+/-} T790M mutation in EGFR but not cell lines harboring wild-type or exon 19 deletions. In a humanized xenograft mouse model of NSCLC, EGFRapt decreased tumor burden compared to controls when delivered intratumorally over multiple doses. To elucidate the mechanism by which EGFRapt exerts these effects, we monitored cellular processes associated with kinase-dependent and kinase-independent mechanisms and found that the anti-cancer effects of EGFRapt are cell line dependent, inhibiting cellular proliferation in one cell line and inducing cell death in another. Post hoc transcriptomics analysis supported these findings and provided additional mechanistic insights. Overall, these data establish that EGFRapt has direct anti-cancer activity in mutant EGFR positive NSCLC via targetable mechanisms that are independent of existing approaches, and they provide a foundation for further development of nucleic acid-based therapies that target EGFR.

cancer biology↗

bioRxiv2018

Activation of innate immune responses by a CpG oligonucleotide sequence composed entirely of threose nucleic acid.

Recent advances in synthetic biology have led to the development of nucleic acid polymers with backbone structures distinct from those found in nature, termed xeno-nucleic acids (XNAs). Several unique properties of XNAs make them attractive as nucleic acid therapeutics, most notably their high resistance to serum nucleases and ability to form Watson-Crick base-pairing with DNA and RNA. The ability of XNAs to induce immune responses has not been investigated. Threose nucleic acid (TNA), a type of XNA, is recalcitrant to nuclease digestion and capable of undergoing Darwinian evolution to produce high affinity aptamers; thus, TNA is an attractive candidate for diverse applications, including nucleic acid therapeutics. Here, we evaluated a TNA oligonucleotide derived from a CpG oligonucleotide sequence known to activate TLR9-dependent immune signaling in B cell lines. We observed a slight induction of relevant mRNA signals, robust B cell line activation, and negligible effects on cellular proliferation.

synthetic biology↗