The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK -Rearranged Lung Cancer
Open accessAbstract
Advanced, anaplastic lymphoma kinase (ALK)–positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALKG1202R, increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant. Significance: Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib. These findings highlight the importance of repeat biopsies and genotyping following disease progression on targeted therapies, particularly second-generation ALK inhibitors. Cancer Discov; 6(10); 1118–33. ©2016 AACR. See related commentary by Qiao and Lovly, p. 1084. This article is highlighted in the In This Issue feature, p. 1069
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Self-citationCrizotinib versus Chemotherapy in Advanced ALK -Positive Lung Cancer
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Self-citationFirst-Line Crizotinib versus Chemotherapy in ALK -Positive Lung Cancer
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Self-citationAlectinib versus Crizotinib in Untreated ALK -Positive Non–Small-Cell Lung Cancer
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Metadata
- Authors
- Gainor, J. F., Dardaei, L., Yoda, S., Friboulet, L., Leshchiner, I., Katayama, R., Dagogo-Jack, I., Gadgeel, S., Schultz, K., Singh, M., Chin, E., Parks, M., Lee, D., DiCecca, R. H., Lockerman, E., Huynh, T., Logan, J., Ritterhouse, L. L., Le, L. P., Muniappan, A., Digumarthy, S., Channick, C., Keyes, C., Getz, G., Dias-Santagata, D., Heist, R. S., Lennerz, J., Sequist, L. V., Benes, C. H., Iafrate, A. J., Mino-Kenudson, M., Engelman, J. A., & Shaw, A. T.
- Venue
- Cancer Discovery
- Published
- 2016-10-01
- Volume
- 6
- Issue
- 10
- Pages
- 1118-1133
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2482427906
- Cited by
- 1,148
- References
- 13
- FWCI
- 99.57
- Type
- journal article
- Language
- en
- Open access
- green
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- Gainor, J. F., Dardaei, L., Yoda, S., Friboulet, L., Leshchiner, I., Katayama, R., Dagogo-Jack, I., Gadgeel, S., Schultz, K., Singh, M., Chin, E., Parks, M., Lee, D., DiCecca, R. H., Lockerman, E., Huynh, T., Logan, J., Ritterhouse, L. L., Le, L. P., . . . Shaw, A. T. (2016). Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK -Rearranged Lung Cancer. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-16-0596
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