Autophagosome-Mediated EGFR Down-Regulation Induced by the CK2 Inhibitor Enhances the Efficacy of EGFR-TKI on EGFR-Mutant Lung Cancer Cells with Resistance by T790M

• DOI: 10.1371/journal.pone.0114000
• Publication Date: 2014-12-08T18:52:33Z
• Authors: Kwang Sup So; Cheol Hyeon Kim; Jin Kyung Rho; Sun Ye Kim; Yun Jung Choi; Joon Seon Song; Woo Sung Kim; Chang Min Choi; Young Jin Chun; Jae Cheol Lee
• Keywords: T790M; Autophagosome; EGFR Inhibitors; Growth inhibition

Protein kinase CK2 has diverse functions promoting and maintaining cancer phenotypes. We investigated the effect of inhibition in lung cells with T790M-mediated resistance to EGFR-TK inhibitor. Resistant sublines PC-9 gefitinib (PC-9/GR) erlotinib (PC-9/ER) were established by previous study, T790M secondary mutation was found both resistant sublines. A decrease EGFR siRNA treatment effectively controlled growth cells, thus suggesting that they still have EGFR-dependency. CX-4945, a potent selective inhibitor, induced autophagy PC-9/GR PC-9/ER, which supported induction autophagic vacuoles microtubule-associated protein 1 light chain 3 (LC3) expression, increase punctate fluorescent signals pre-transfected green (GFP)-tagged LC3. However, withdrawal CX-4945 led recovery autophagy. dependent using small interfering RNA against CK2. The alone minimal cells. combined EGFR-TKI inhibited cancer-cell proliferation apoptosis. increased translocation from cell surface into autophagosome, subsequently leading while 3MA or Atg7-targeted pretreatment reduced CX-4945. Accordingly, apoptosis combination suppressed pretreatment, autophagosome-mediated down-regulation would an important role regarding apoptotic death EGFR-TKI. Combined inhibitor may be promising strategy for overcoming resistance.