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

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).

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

(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

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.