Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2022 Nov 23:13:1060460.
doi: 10.3389/fphar.2022.1060460. eCollection 2022.

Primary resistance to first- and second-generation ALK inhibitors in a non-small cell lung cancer patient with coexisting ALK rearrangement and an ALK F1174L-cis-S1189C de novo mutation: A case report

Jiuzhou Zhao  1   2 , Xiang Li  1 , Ruizhe Fan  1 , Yaping Qin  3 , Zhizhong Wang  1   2 , Bo Wang  1   2 , Shaomei Li  4 , Jianfeng Fan  5 , Xinxin Wu  1   2 , Hongxia Liu  1   2 , Yuping Guan  1 , Yinfeng Liang  1 , Xiao Zhang  4 , Yongjun Guo  1   2
Affiliations
Case Reports

Primary resistance to first- and second-generation ALK inhibitors in a non-small cell lung cancer patient with coexisting ALK rearrangement and an ALK F1174L-cis-S1189C de novo mutation: A case report

Jiuzhou Zhao et al. Front Pharmacol. .

Abstract

The effectiveness of the tyrosine kinase inhibitor ALK (TKI) for non-small cell lung cancer has been confirmed. However, resistance to ALK-TKIs seems inevitable. Mutations in the ALK kinase domain have been reported as an important mechanism of acquired resistance to ALK therapy. However, patients with de novo ALK kinase domain mutations and ALK rearrangements who were not treated with ALK inhibitors have rarely been reported. Here, we report a case of primary drug resistance to first- and second-generation ALK inhibitors in a NSCLC patient with ALK-rearrangement. The next-generation sequencing test of the pathological biopsy showed that the de novo ALK kinase domain mutation F1174L-cis-S1189C may be the cause of primary drug resistance.

Keywords: EML4-ALK; F1174L; S1189C; de novo mutation; next generation sequencing (NGS); non-small cell lung cancer (NSCLC).

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
(A–F) CT scan showed the changes in the lung mass in the patient PRE- and POST-treatment (G) The CT scan revealed an atrial filling defect. (H,I) MRI and PET-CT showed no metastasis in brain and bone.
FIGURE 2
FIGURE 2
(A) Hematoxylin-eosin staining (HE) (B–E) Immunohistochemistry analysis revealed immunoreactivity to CK (B), TTF-1 (C), Ki-67 (D), and ALK-D5F3 (E). (F) The rebiopsy analysis revealed immunoreactivity to ALK-D5F3 (F).
FIGURE 3
FIGURE 3
NGS analyses before and after therapy. NGS analysis before crizotinib treatment revealed the presence of the ALK fusion (A) plus the F1174L-cis-S1189C mutation (B). NGS analysis after crizotinib and ceritinib treatment revealed the presence of the ALK fusion (C) plus the F1174L-cis-S1189C mutation (D). (E) ALK structure retrieved from PDB 2XP2. In silico mutagenesis of human ALK binding to three ALK inhibitor complexes (PDB ID: 2XP2, PDB ID: 4MKC, and PDB ID: 3AOX) was used to predict the variable influence on protein stability. The dStability and relative thermostability of the mutation with respect to the wild-type protein are shown in the table.
See this image and copyright information in PMC

References

    1. Amin A. D., Li L., Rajan S. S., Gokhale V., Groysman M. J., Pongtornpipat P., et al. (2016). TKI sensitivity patterns of novel kinase-domain mutations suggest therapeutic opportunities for patients with resistant ALK+ tumors. Oncotarget 7 (17), 23715–23729. 10.18632/oncotarget.8173 - DOI - PMC - PubMed
    1. Azarova A. M., Gautam G., George R. E. (2011). Emerging importance of ALK in neuroblastoma. Semin. Cancer Biol. 21 (4), 267–275. 10.1016/j.semcancer.2011.09.005 - DOI - PMC - PubMed
    1. Camidge D. R., Kim H. R., Ahn M. J., Yang J. C., Han J. Y., Lee J. S., et al. (2018). Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N. Engl. J. Med. 379 (21), 2027–2039. 10.1056/NEJMoa1810171 - DOI - PubMed
    1. Choi Y. L., Soda M., Yamashita Y., Ueno T., Takashima J., Nakajima T., et al. (2010). EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N. Engl. J. Med. 363 (18), 1734–1739. 10.1056/NEJMoa1007478 - DOI - PubMed
    1. Doebele R. C., Pilling A. B., Aisner D. L., Kutateladze T. G., Le A. T., Weickhardt A. J., et al. (2012). Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin. Cancer Res. 18 (5), 1472–1482. 10.1158/1078-0432.Ccr-11-2906 - DOI - PMC - PubMed

Publication types

LinkOut - more resources