Autophagy is not uniformly cytoprotective: a personalized medicine approach for autophagy inhibition as a therapeutic strategy in non-small cell lung cancer.
Lung cancer is the leading cause of cancer-related death worldwide. In addition to surgical resection, which is considered first-line treatment at early stages of the disease, chemotherapy and radiation are widely used when the disease is advanced. Of multiple responses that may occur in the tumor cells in response to cancer therapy, the functional importance of autophagy remains equivocal; this is likely to restrict current efforts to sensitize this malignancy to chemotherapy and/or radiation by pharmacological interference with the autophagic response.



In this review, we attempt to summarize the current state of knowledge based on studies that evaluated the function of autophagy in non-small cell lung cancer (NSCLC) cells in response to radiation and the most commonly used chemotherapeutic agents.



In addition to the expected prosurvival function of autophagy, where autophagy inhibition enhances the response to therapy, autophagy appears also to have a "non-cytoprotective" function, where autophagy blockade does not affect cell viability, clonogenicity or tumor volume in response to therapy. In other cases, autophagy may actually mediate drug action via expression of its cytotoxic function.



These observations emphasize the complexity of autophagy function when examined in different tumor cell lines and in response to different chemotherapeutic agents. A more in-depth understanding of the conditions that promote the unique functions of autophagy is required in order to translate preclinical findings of autophagy inhibition to the clinic for the purpose of improving patient response to chemotherapy and radiation.
Department of Pharmacology and Toxicology, Massey Cancer Center, Virginia Commonwealth University, 401 College St., Richmond, VA 23298, United States.
Tareq
T
Saleh
Department of Radiation Oncology, Virginia Commonwealth University, Henrico Doctor's Hospital, 1602 Skipwith Rd, Richmond, VA 23229, United States.
Laurie
L
Cuttino
Department of Pharmacology and Toxicology, Massey Cancer Center, Virginia Commonwealth University, 401 College St., Richmond, VA 23298, United States; Department of Medicine, Massey Cancer Center, Virginia Commonwealth University, 401 College St., Richmond, VA 23298, United States. Electronic address: gewirtz@vcu.edu.
David A
DA
Gewirtz
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001343:Autophagy / Q000187:drug effects* / Q000528:radiation effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D049109:Cell Proliferation / Q000187:drug effects* / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D057285:Precision Medicine
D000970:Antineoplastic Agents
Apoptosis; Autophagy; Chemotherapy; Non-Small cell lung cancer; Non-cytoprotective; Radiation; Sensitization