Abstract
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.
Highlights
Rearrangements in the anaplastic lymphoma kinase (ALK) gene have been found in 3%–7% lung adenocarcinomas [1, 2]
The subline with acquired resistance to crizotinib included two clones (H3122/ CR-1 and H3122/CR-2) from H3122, whereas the subline with acquired resistance to TAE684 consisted of only one clone (H2228/TR) from H2228 because H2228 cells did not form colonies
Resistant cells showed cross-resistance to other ALK inhibitors, including ceritinib and alectinib, they showed no cross-resistance to AUY922, a HSP90 inhibitor (Table 1)
Summary
Rearrangements in the anaplastic lymphoma kinase (ALK) gene have been found in 3%–7% lung adenocarcinomas [1, 2]. Similar to the T790M mutation in EGFR-TKI therapy, many secondary mutations such as L1196M, L1152R, C1156Y, and F1174L, which hinder drug binding, have been identified in crizotinib-resistant samples [5, 7]. The second-generation ALK inhibitors ceritinib and alectinib have shown promising clinical activity in ALK-positive lung cancer [8,9,10,11] and have received FDA approval for the treatment of crizotinibrefractory, ALK-rearranged lung cancer. In preclinical studies, these novel ALK inhibitors were able to overcome many crizotinib-resistant ALK mutations [7, 12, 13]. There are no identifiable secondary mutations in approximately twothirds of the cases where resistance to ALK inhibitors is observed [5, 7]
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