title: Immunohistochemical evidence for the association between attenuated mTOR signaling and diffuse alveolar damage, a fatal lung complication.
abstract: Targeted anticancer therapies have been developed to interfere with specific target molecules including those of downstream pathways required for tumor growth and progression. Mammalian target of rapamycin (mTOR) has been considered as one of the target molecules of cancer growth, and its inhibitors have been reported to exert an anticancer effect in various malignant tumors. The pulmonary disorder is one of the major side effects of anticancer drugs including mTOR inhibitor (mTORi), and the diagnosis of lung injury induced by medication is difficult because of non-specific nature of the radiological findings. In this study, we present the detailed autopsy findings of a patient who developed diffuse alveolar damage (DAD) following mTORi treatment for metastatic renal cell carcinoma. We also studied 19 cases of DAD derived from other diseases and 9 cases with non-pathological lung. Of interest, pneumocytes of the patients with DAD, who received other anticancer drugs or contacted bacteria, demonstrated significantly lower mTOR activities than pneumocytes of those with non-pathological lung tissue, as judged by the immunohistochemical analysis. In contrast, both pneumocytes and T cells in DAD tissues of the patient treated with mTORi showed higher mTOR activities than those of patients with DAD of other causes, suggesting that the enhanced mTOR signaling may be involved in the development of DAD after mTORi treatment. This unexpected finding needs to be confirmed in other patients treated with mTORi. In conclusion, the attenuated mTOR signaling in pneumocytes may contribute to the pathogenesis of DAD in patients without mTORi treatment.
authors.affiliation: Department of Pathology, Tohoku University School of Medicine.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Saito
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Yanai
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Miki
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Fukasawa
authors.forename: Junya
authors.initials: J
authors.lastname: Tominaga
authors.forename: Masahito
authors.initials: M
authors.lastname: Ebina
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism; D000704:Analysis of Variance; D001344:Autopsy; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D000068338:Everolimus; D017809:Fatal Outcome; D006801:Humans; D007150:Immunohistochemistry; D008171:Lung Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011650:Pulmonary Alveoli / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018709:Statistics, Nonparametric; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus