Multiple receptor tyrosine kinase activation related to ALK inhibitor resistance in lung cancer cells with ALK rearrangement
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Se Hoon Choi1, Dong Ha Kim2,3, Yun Jung Choi2,3, Seon Ye Kim2,3, Jung-Eun Lee2,3, Ki Jung Sung2,3, Woo Sung Kim2, Chang-Min Choi2,4, Jin Kyung Rho2,3,5,* and Jae Cheol Lee4,*
1Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea
2Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea
3Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea
4Department of Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea
5Department of Convergence Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea
*These authors have contributed equally to this work
Jin Kyung Rho, email: email@example.com
Jae Cheol Lee, email: firstname.lastname@example.org
Keywords: ALK, resistance, EGFR, IGF1R, lung cancer
Received: February 08, 2017 Accepted: March 22, 2017 Published: May 08, 2017
The activation of alternative receptor tyrosine kinases (RTKs) is known to mediate resistance to ALK inhibitors. However, the role of multiple RTK activation in resistance has yet to be determined. Two crizotinib-resistant (H3122/CR-1 and H3122/CR-2) and one TAE684-resistant (H2228/TR) cell lines were established. Multi-RTK arrays and Western blots were performed to detect the activation of bypass signals. There were no secondary mutations in the sequencing. EGFR and MET were activated in H3122/CR-1 cells whereas EGFR and IGF1R were activated in H3122/CR-2 cells. Concomitant activation of MET did not contribute to resistance as crizotinib completely suppressed both p-MET and p-ALK in H3122/CR-1 cells, whose survival was not affected by crizotinib. However, combined inhibition of EGFR and ALK was effective in controlling this resistant cell line. In H3122/CR-2 cells, the inhibition of both ALK and IGF1R could effectively suppress cell growth, whereas simultaneous inhibition of ALK and EGFR brought about a less-effective suppression, indicating that IGF1R activation is the main resistance mechanism. H2228/TR cells showed activation of the HER family (EGFR, ErbB2, and ErbB3). Afatinib, a pan-HER inhibitor, was more potent in suppressing resistant cells than gefitinib when combined with crizotinib, which suggests that coactivation of ErbB2 and ErbB3 also contributes to resistance. Interestingly, all three resistant cell lines responded well to AUY922, which can inhibit ALK, EGFR, and IGF1R activity. Activation of multiple RTKs can occur during acquired resistance to ALK inhibitors, in which case the dominant or significant bypass signal should be identified to provide a more appropriate combination therapy.
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