Page 39 - Hormel Report 2021

Figure 1: EGFR-mutated lung adenocarcinoma patients exhibit increased DARPP-32 protein expression (brown immunostaining) upon EGFR inhibitor refractory disease progression. Representative DARPP-32 immunostaining in specimens derived from the same patient before treatment and after development of EGFR inhibitor resistance.
Combating non-small cell lung cancer resistance to targeted therapy
Many non-small cell lung cancer patients are diagnosed with advanced disease and tested for specific tumor-causing mutations, including those that frequently occur in a gene called EGFR (i.e. epidermal growth factor receptor). EGFR mutation positive advanced stage lung cancer patients benefit
from treatment with drugs designed to inhibit EGFR signaling. Unfortunately, most patients develop resistance to these drugs within 12-18 months and rapid cancer progression recurs. New approaches to predict and prevent acquired resistance to EGFR inhibitors are urgently needed. We have shown that DARPP-32 is upregulated as lung cancer patients develop resistance to EGFR inhibitors (Figure 1). This project is admirably led by Dr. Sk. Kayum Alam, who is supported by a generous Fifth District Eagles Telethon Postdoc Award. We recently discovered a DARPP-32-mediated, ERBB3-dependent mechanism lung cancer cells use to evade EGFR inhibitor-induced cell death, potentially paving the way for the development of therapies to better combat therapy-refractory lung cancer progression (Oncogene, 2021).
Vascular permeability in cardiovascular disease, cancer, and COVID-19-associated acute lung injury
Vascular permeability triggered by inflammation or ischemia promotes edema, exacerbates disease progression, and impairs tissue recovery. Vascular permeability is induced by a protein called VEGF (i.e. vascular endothelial growth factor). Given the prominent role of VEGF in promoting pathologies associated with cancer,
stroke, cardiovascular disease, retinal conditions, and COVID-19-associated acute lung injury, inhibiting vascular permeability mediated by VEGF and inflammation is an important therapeutic pursuit. We have shown that VEGF mediates vascular permeability through a protein called STAT3 (Figure 2), and thus, targeting the
Identifying a new post-exposure therapeutic window to reduce UV-induced skin damage The negative health consequences of acute ultraviolet (UV) exposure are evident, with reports
of 30,000 emergency room visits annually to treat the effects of sunburn in the United States alone. While the pain associated with the acute effects of sun-burn may be relieved by current interventions, existing post-sunburn treatments are not capable of reversing the cumulative pathological effects. We have shown that activation of VEGF signaling is necessary for the initiating the acute pathological effects of sunburn. Our findings suggest targeting VEGF signaling may reduce the subsequent inflammation and pathology associated with UV-induced skin damage, which reveals a new post-exposure therapeutic window to potentially inhibit the known detrimental effects of UV on human skin (Mayo Clinic Proceedings, 2021).
Figure 2: Inhibition of STAT3 stabilizes endothelial cell junctions (green) following VEGF stimulation in human endothelial cells. VEGF stimulation de- stabilizes junctions (yellow arrows). STAT3 inhibitor treatment restores endothelial cell junction stability (pink arrows) follow- ing VEGF treatment. Scale bar: 20 μm.
STAT3 signaling cascade represents a promising strategy to reduce pathological effects of permeability during cancer, cardiovascular disease, and lung injury.
We have used a variety of in vitro and in vivo models to understand the molecular basis of STAT3-regulated permeability.
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Publications:
• Alam SK, Zhang Y, Wang L, Zhu Z, Hernandez CE, Zhou Y, Yang N, Lei J, Chen X, Zeng L, Klein MA, Hoeppner LH. DARPP-32
promotes ERBB3-mediated resistance to molecular targeted therapy in EGFR-mutated lung adenocarcinoma. Oncogene. 2021. https://doi. org/10.1101/2021.02.12.430856
• Hartono SP, Bedell VM, Alam SK, O’Gorman M, Serres M, Hall SR, Pal K, Kudgus RA, Mukherjee P, Seelig DM, Meves A, Mukhopadhyay D, Ekker SC, Hoeppner LH. Vascular endothelial growth factor as an immediate-early activator of UV-induced skin injury. Mayo Clinic Proceedings. 2021. https://doi.org/10.1101/2020.07.13.198549
• Wang L, Astone M, Alam SK, Zhu Z, Pei W, Frank DA, Burgess SM, Hoeppner LH. Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability. Pending Revisions: Disease Models & Mechanisms. 2021. PMID: 33140053