Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells

// Azusa Tanimoto 1 , Tadaaki Yamada 1 , Shigeki Nanjo 1 , Shinji Takeuchi 1 , Hiromichi Ebi 1 , Kenji Kita 1 , Kunio Matsumoto 2 and Seiji Yano 1 1 Divisions of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan 2 Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan Correspondence: Seiji Yano, email: // Keywords : Hsp90 inhibitor, EML4-ALK, drug resistance, receptor ligands, New generation ALK inhibitor. Received : April 1, 2014 Accepted : June 1, 2014 Published : June 3, 2014 Abstract Alectinib is a new generation ALK inhibitor with activity against the gatekeeper L1196M mutation that showed remarkable activity in a phase I/II study with echinoderm microtubule associated protein-like 4 ( EML4 ) - anaplastic lymphoma kinase ( ALK ) non-small cell lung cancer (NSCLC) patients. However, alectinib resistance may eventually develop. Here, we found that EGFR ligands and HGF, a ligand of the MET receptor, activate EGFR and MET, respectively, as alternative pathways, and thereby induce resistance to alectinib. Additionally, the heat shock protein 90 (Hsp90) inhibitor suppressed protein expression of ALK, MET, EGFR, and AKT, and thereby induced apoptosis in EML4-ALK NSCLC cells, even in the presence of EGFR ligands or HGF. These results suggest that Hsp90 inhibitors may overcome ligand-triggered resistance to new generation ALK inhibitors and may result in more successful treatment of NSCLC patients with EML4-ALK.