Eukaryotic translation initiation factor 3 subunit C is associated with acquired resistance to erlotinib in non-small cell lung cancer.

The acquisition of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) is one of the major problems in the pharmacotherapy against non-small cell lung cancers; however, molecular mechanisms remain to be fully elucidated. Here, using a newly-established erlotinib-resistant cell line, PC9/ER, from PC9 lung cancer cells, we demonstrated that the expression of translation-related molecules, including eukaryotic translation initiation factor 3 subunit C (eIF3c), was upregulated in PC9/ER cells by proteome analyses. Immunoblot analyses confirmed that eIF3c protein increased in PC9/ER cells, compared with PC9 cells. Importantly, the knockdown of eIF3c with its siRNAs enhanced the drug sensitivity in PC9/ER cells. Mechanistically, we found that LC3B-II was upregulated in PC9/ER cells, while downregulated by the knockdown of eIF3c. Consistently, the overexpression of eIF3c increased the number of autophagosomes, proposing the causality between eIF3c expression and autophagy. Moreover, chloroquine, an autophagy inhibitor, restored the sensitivity to erlotinib. Finally, immunohistochemical analyses of biopsy samples showed that the frequency of eIF3c-positive cases was higher in the patients with EGFR-TKI resistance than those prior to EGFR-TKI treatment. Moreover, the eIF3c-positive cases exhibited poor prognosis in EGFR-TKI treatment. Collectively, the upregulation of eIF3c could impair the sensitivity to EGFR-TKI as a novel mechanism of the drug resistance.

Can cinacalcet replace parathyroid intervention in severe secondary hyperparathyroidism?

A 6-month observational study was conducted in 61 patients (33 men and 28 women, mean age 54.8 +/- 12.4 years) treated with cinacalcet in whom parathyroid intervention was indicated. Thirty-seven patients had baseline intact parathyroid hormone (iPTH) levels of >500 pg/mL, but only five still had levels this high after 6-month cinacalcet therapy. No patients had phosphorus (P), calcium (Ca), or iPTH levels within the target range at baseline, but six patients (9.8%) reached all three target ranges after treatment. The stratum with many patients who had 2-4 enlarged parathyroid glands shifted toward the low PTH groups (iPTH < 300 pg/mL) with treatment. There was less of a tendency for patients with more enlarged glands, that is, 10 mm or larger at baseline, to have a higher PTH level after cinacalcet treatment. There was no significant difference in the total volume of parathyroid glands after treatment, since some glands enlarged while others shrank. These findings indicate cinacalcet to be a potentially useful treatment. Our results suggest that 80% of cases indicated for parathyroid intervention could avoid such interventional therapies with cinacalcet administration. However, the variability in the gland-shrinking effect of cinacalcet on parathyroid glands merits further study.