Tumor-Targeted Nanoparticles Deliver a Vitamin D-Based Drug Payload for the Treatment of EGFR Tyrosine Kinase Inhibitor-Resistant Lung Cancer.
Chang LiuTatiana ShaurovaSuzanne ShoemakerMartin PetkovichPamela A HershbergerYun WuPublished in: Molecular pharmaceutics (2018)
Mutation in the tyrosine kinase (TK) domain of the epidermal growth factor receptor ( EGFR) gene drives the development of lung cancer. EGFR tyrosine kinase inhibitors (EGFR TKIs), including erlotinib and afatinib, are initially effective in treating EGFR mutant nonsmall cell lung cancer (NSCLC). However, drug resistance quickly develops due to several mechanisms, including induction of the epithelial-mesenchymal transition (EMT). No effective therapies are currently available for patients who develop EMT-associated EGFR TKI resistance. 1,25-Dihydroxyvitamin D3 (1,25D3) promotes epithelial differentiation and inhibits growth of NSCLC cells. 1,25D3 thus represents a promising agent for the treatment of EMT-associated EGFR TKI resistance. However, 1,25D3 induces the expression of 24-hydroxylase (24OHase), which decreases 1,25D3 activity. CTA091, a potent and selective 24OHase inhibitor, has been developed to attenuate this adverse effect. CTA091 also suppresses renal 24OHase activity and so may promote hypercalcemia. To exploit favorable effects of 1,25D3 plus CTA091 in tumor cells while avoiding problematic systemic effects of 24OHase inhibition, we developed EGFR-targeted, liposomal nanoparticles (EGFR-LP) to offer tumor-targeted co-delivery of 1,25D3 and CTA091. We then established an EMT-associated model of EGFR TKI resistance, and showed that such nanoparticles improved cellular uptake of 1,25D3 and CTA091, drove pro-epithelial signaling by upregulating E-cadherin ( CDH1), and significantly inhibited the growth of EGFR TKI resistant cells. Our results demonstrated that the delivery of vitamin D-based drug payloads via tumor-targeted EGFR-LP has promise as a new therapy for EFGR TKI resistant lung cancer. Future studies will focus on in vivo evaluation of biological activity, therapeutic benefits, and systemic toxicity prior to clinical translation.
Keyphrases
- epidermal growth factor receptor
- tyrosine kinase
- advanced non small cell lung cancer
- small cell lung cancer
- epithelial mesenchymal transition
- signaling pathway
- induced apoptosis
- stem cells
- poor prognosis
- single cell
- dna methylation
- transforming growth factor
- drug delivery
- gene expression
- long non coding rna
- anti inflammatory
- cell proliferation
- machine learning
- adverse drug
- combination therapy
- transcription factor
- cell cycle arrest
- copy number
- electronic health record
- replacement therapy
- cell death