Ceritinib Aggravates Glycemic Control in Insulin-treated Patients with Diabetes and Metastatic ALK-positive Lung Cancer

Abstract

We herein report a 75-year-old woman with insulin-treated diabetes and metastatic anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who received ceritinib, a second-generation ALK inhibitor, and achieved dramatic tumor reduction. However, her fasting blood glucose increased, particularly markedly in the first two weeks after ceritinib administration, and did not normalize even increasing the total insulin dose. After discontinuing ceritinib, her glucose levels rapidly reduced. Ceritinib can aggravate hyperglycemia in patients with diabetes who lack compensatory insulin secretion, due to its inhibitory effects on the insulin receptor. Careful monitoring for ceritinib-induced hyperglycemia should be performed, especially in the first two weeks after ceritinib administration.

Keywords: ceritinib; hyperglycemia; insulin resistance.

Figure 1.

Clinical management of a patient with metastatic anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). The figure shows several lines of therapy received by the patient for metastatic ALK-rearranged NSCLC as well as the duration of each treatment. Computed tomography during the incipient stage revealed one nodular lesion each in both the left and right lobes (arrows). The metastatic liver lesions (arrowheads) were drastically reduced by ceritinib administration.

Figure 2.

(A) Hematoxylin and Eosin staining of the resected left lung tumor showed papillary adenocarcinoma. (B) Immunohistochemistry of ALK using the intercalated antibody-enhanced polymer (iAEP) method revealed the protein expression in the tumor cells.

Figure 3.

The profile of insulin treatment and its management before and after ceritinib administration. The day that ceritinib administration was started is defined as day 0. The fasting glucose levels and insulin therapy during ceritinib treatment are indicated. The fasting glucose levels were evaluated based on pre-breakfast self-measured blood glucose levels. The fasting glucose levels drastically increased after two weeks of ceritinib administration. After ceritinib discontinuation, the patient’s glucose levels rapidly declined, and the insulin dose was able to be reduced, despite continued prednisolone (PSL) treatment.

Figure 4.

The comparison of the amino acid residues in the ATP-binding and DFG motif-1 sites between anaplastic lymphoma kinase (ALK) and the insulin receptor (INSR). The similarities in the amino acid sequences around the ATP-binding site and DFG motif-1 between ALK and INSR are shown. Matched amino acid residues are highlighted in yellow. The gatekeeper and DFG motif-1 of ALK are L1196 and G1269 (indicated with red), respectively. Ceritinib binds to ¹¹⁹⁸LMA¹²⁰⁰, known as the triad hinge of ALK as well as a key site for ATP binding (indicated by a blue box). The DFG motif-1 and LMA triad hinge are highly conserved between ALK and the INSR, aside from the difference in the gatekeeper (L1196 for ALK and M1103 for INSR).