A 72-year-old woman, with BMI 30 kg/m2, had established type 2 diabetes for 2 years before her diagnosis of non–small cell lung cancer (NSCLC). Initially, her HbA1c (A1C) was 10.3%. After treatment with pioglitazone and glyburide for 1 year, she attained an A1C of 8.2%, with average fasting glucose levels of 130–160 mg/dl. She presented to our care with metastatic NSCLC. After two cycles of chemotherapy with carboplatin and paclitaxel, her tumor progressed, and subsequently her treatment was changed to 150 mg erlotinib once a day. Within the first 4 weeks of erlotinib use, the patient noted frequent episodes of hypoglycemia, and her premeal glucose levels decreased to <90 mg/dl. Notably, her appetite and nutritional intake were not changed, her weight remained stable, and no other medications known to affect glucose metabolism had been introduced. A morning cortisol level and renal and hepatic functions were also found to be normal. Glyburide at 10 mg twice a day was eventually discontinued. Her fasting glucose levels stabilized at ∼90–110 mg/dl. The patient achieved a small reduction in the size of her tumor burden with erlotinib. After 8 months of erlotinnib therapy, and while continuing 30 mg pioglitazone once a day, her A1C was measured at 6.5%. Unfortunately, 1 month later, symptomatic leptomeningeal central nervous system lesions progressed and the patient was transferred to a hospice program.
Erlotinib (Tarceva; OSI Pharmaceuticals) is an analinoquinazolone inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase and has been approved as second-line treatment in NSCLC (1). Hypoglycemia or glucose derangements were not reported as side effects in the phase III randomized trial (1) or in the available literature of these specific tyrosine kinase inhibitors (2). However, of interest to this case, the crystal structure of the kinase activation loop of EGFR adopts a conformation similar to that of the phosphorylated active form of the kinase domain of the insulin receptor (3). Downstream targets of EGFR, such as Akt (protein kinase B) and extracellular signal–regulated kinase, are also involved in the complex pathway of insulin signaling (4). Of note, regression of type 2 diabetes has been described with the use of another tyrosine kinase inhibitor, imatinib mesylate (Gleevec; Novartis) (5). Further investigation of the possible connection of EGFR-mediated pathways active in cancer and in the pathogenesis of diabetes as well as the possible use of analinoquinazolone EGFR inhibitor compounds in hyperglycemic states may be warranted.
