| Autor: |
Aaron N. Hata, Alice T. Shaw, Justin F. Gainor, Michael S. Lawrence, Christopher G. Azzoli, Cyril H. Benes, Rebecca J. Nagy, Ashish Saxena, Subba R. Digumarthy, Sara E. Stevens, Hetal D. Marble, Andrew Do, Emily Chin, Beow Y. Yeap, Nathaniel A. Adams, Audris Oh, Kylie Prutisto-Chang, Marguerite M. Rooney, Jessica J. Lin, Adam Langenbucher, Jochen K. Lennerz, Satoshi Yoda, Ibiayi Dagogo-Jack |
| Rok vydání: |
2023 |
| DOI: |
10.1158/1078-0432.c.6529973.v1 |
| Popis: |
Purpose:Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed.Experimental Design:We performed FISH and/or next-generation sequencing on 207 posttreatment tissue (n = 101) or plasma (n = 106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance.Results:MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib (P = 0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid responses to ALK/MET combination therapy.Conclusions:Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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