Office of VP for Research
Lung cancer is the deadliest and most frequently diagnosed type of tumor worldwide, with 1.6 million deaths reported annually. Despite administration of standard chemotherapeutic agents with evolving systemic cancer therapies directed at driver mutations (EGFR, BRAF and ALK), inhibiting angiogenesis (anti-VEGF therapy), and immune-checkpoint blockade (anti-PD-1, anti-PDL1), prognoses remain dreadful due to the large number of patients diagnosed with advanced stage disease and the development of resistance to current therapies. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the recommended first-line therapy for the ~10% of NSCLC patients positive for an EGFR mutation. Although NSCLC patients with an activating EGFR mutation initially respond well to first-line EGFR TKIs, NSCLC inevitably progresses in most patients after 9 to 12 months of treatment. Thus, better treatment options to overcome EGFR TKI resistance are necessary.
Dopamine and cAMP-regulated phophoprotein Mr 32000 (DARPP-32), and its truncated splice variant named t-DARPP, have been shown to promote resistance to EGFR TKIs in gastric cancer and stimulate EGFR activation in breast tumors, respectively. In a variety of adenocarcinomas, aberrant elevation of DARPP-32 and t-DARPP has been shown to promote cancer cell proliferation, survival, and invasion. Recent work reveals DARPP-32 and t-DARPP promote lung tumor growth in orthotopic mouse models. Correspondingly, human NSCLC patient data suggests DARPP-32 is a negative prognostic marker associated with increasing stages of NSCLC and may represent a novel therapeutic target. Therefore, the central theory of this research is that DARPP-32 and t-DARPP drive lung cancer initiation and growth by promoting oncogenic signaling that enables EGFR-mutant NSCLC cells to acquire resistance to molecular targeted EGFR kinase inhibitors.
Genetic DARPP-32 knockout mice and wildtype counterparts will be compared in a mouse model that spontaneously develops EGFR-mutant lung cancer to understand the role of DARPP-32 in NSCLC initiation. DARPP-32 and t-DARPP protein expression will be pathologically evaluated in tumor tissue from EGFR-mutation positive NSCLC patients before EGFR TKI treatment and after development of resistance. DARPP-32 isoforms will be genetically modulated in EGFR inhibitor-sensitive and -resistant NSCLC cells to molecularly understand how DARPP-32 regulates resistance. Finally, adeno-associated virus (AAV)-based gene therapy will be used to inhibit DARPP-32 proteins exclusively in lung tumor cells. A similar approach of AAV-directed shRNA-mediated ablation of hepatitis C virus in hepatocytes has proven to be a safe and effective treatment strategy in animals and humans. The first FDA-approved AAV gene therapy will soon enter the U.S. market to restore vision in patients diagnosed with a genetic form of retinal dystrophy. Collectively, this research will lay the groundwork for the development of therapies designed to circumvent TKI refractory NSCLC progression to improve the quality of life and clinical outcome for patients.