Epidermal growth factor receptor-targeted immunomagnetic liposomes for circulating tumor cell enumeration in non-small cell lung cancer treated with epidermal growth factor receptor-tyrosine kinase inhibitors.

OBJECTIVES: To establish a circulating tumor cell (CTC) enrichment system for non-small cell lung cancer (NSCLC) patients who received first-line treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKI), using EGFR magnetic liposomes (EGFR-ML). MATERIALS AND METHODS: An inverted evaporation method was used to develop antibody modified EGFR-ML. Peripheral blood was collected from NSCLC patients who underwent first-line EGFR-TKI treatment for CTC enumeration. RESULTS: Protein electrophoresis, magnetic saturation curve, and ultraviolet absorption spectrum showed successful incorporation of the EGFR antibody on the surface of the magnetic microspheres, and the development of EGFR-ML was ascertained based on cell morphology and particle size. Using EGFR-ML, CTC were successfully enriched from blood samples and were identified in 77.3% (99/128) of the cohort. When compared to the 21L858R variant, EGFR-19del showed lower CTC counts by EGFR-ML (CTCEGFR). At one month after EGFR-TKI, a lower CTCEGFR was associated with partial response (PR) during treatment (CTCEGFR < 6 vs. ≥ 6/7.5 mL, 75% vs. 49%, P = 0.027). In addition, patients with a lower CTCEGFR at 3 months after EGFR-TKI achieved a longer progression-free survival (PFS) [CTCEGFR < 6 vs. ≥ 6/7.5 mL, 13 months vs. 10.4 months, HR = 2.4, P = 0.042]. CTCEGFR significantly increased at the time of RECIST-progressive disease (RECIST-PD). Representative cases showed that CTCEGFR might increase before and beyond RECIST-PD until no clinical benefit could be acquired from EGFR-TKI. CONCLUSION: We showed that establishing a CTC enrichment system by antibody modified EGFR-ML in NSCLC is feasible. CTC enumeration by EGFR-ML may have the potential to supplement RECIST in dynamically monitoring the response of NSCLC patients' to first-line EGFR-TKI.

EGFR regulates iron homeostasis to promote cancer growth through redistribution of transferrin receptor 1.

Dysregulation in iron metabolism can lead to a wide range of diseases including cancer. Iron-regulatory proteins (IRPs) and iron responsive elements (IREs) have been established as post-transcriptional regulators of intracellular iron homeostasis. The roles of other pathways involved in this process, however, remain largely unknown. Here we report that epidermal growth factor receptor (EGFR), an oncogenic driver, binds to and regulates the subcellular distribution of transferrin receptor 1(TfR1) through its tyrosine kinase activity and thus is required for cellular iron import. Inactivation of EGFR reduces the cell surface TfR1 expression, which leads to decreased iron import due to impaired TfR1-mediated iron uptake. This damaged iron assimilation results in cell cycle arrest and growth inhibition, which can be partially rescued by non-Tf-bound iron supplements. Evaluation of non-small cell lung cancer samples reveals a positive correlation between EGFR activation and membrane TfR1 expression. Our findings uncover a new role of EGFR in modulating cellular iron homeostasis through redistribution of TfR1, which is essential for cancer development and progression.