Autophagy is not uniformly cytoprotective: a personalized medicine approach for autophagy inhibition as a therapeutic strategy in non-small cell lung cancer

Abstract

BACKGROUND 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. SCOPE OF REVIEW 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. MAJOR CONCLUSIONS 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. GENERAL SIGNIFICANCE 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.

TRAP1 regulates autophagy in lung cancer cells

“…In fact, the effectiveness of targeted therapies for cancers is extremely context dependent. For example, the complexity of the role of autophagy in therapeutic responses to therapy in NSCLC has been demonstrated . Furthermore, recent data demonstrated that cytosolic HSP90 and TRAP1 modulate growth and lung metastasis in vivo, although they do not play any role in the initiation of breast cancer.…”

Potentially Functional Variants of ATG16L2 Predict Radiation Pneumonitis and Outcomes in Patients with Non–Small Cell Lung Cancer after Definitive Radiotherapy

“…While radiation-induced autophagy often serves as a protective function in cell culture-based studies, it is still unclear to what an extent autophagy may be induced by radiation in human cancer cells, although the function of autophagy in response to radiation is inconsistent. 23 Some studies reported that autophagy promoted the anticancer effects of radiotherapy; others showed that upregulation of autophagy were associated with tumor resistance in radiation therapy and that blockade of autophagy contributed to the radiosensitization. 24 More recent reports suggested that inhibition of autophagy led to an increased expression of IL1B and IL6 and that autophagy played an important role in tissue inflammatory response.…”

Proteomics Insights into Autophagy

“…CMA is considered to be very selective whereas micro‐autophagy and macro‐autophagy may be selective or non‐selective . In the context of cancer, different forms of autophagy have been identified and have been classified as either cytoprotective, cytotoxic, cytostatic, or non‐protective . This classification applies primarily to the case of autophagy induced in tumor cells in response to therapy whereas basal autophagy is virtually always cytoprotective.…”