Macroautophagy (herein referred to as autophagy) is the process of cytosolic recycling to clear damaged organelles and macromolecules from the cell and supply metabolic processes. Cancer cells exploit autophagy to fuel hyperproliferation and resist cytotoxic chemotherapy. As a result, autophagy inhibition is being investigated as an anti-cancer therapy. In some cases, KRAS-mutant non-small cell lung cancer up-regulates and depends on autophagy for survival. Autophagy may be an especially effective therapeutic target in such cases. However, several gaps in knowledge remain regarding the molecular wiring of autophagy, the relationship between KRAS and autophagy and the clinical development of autophagy inhibitors.
This study investigated autophagy inhibition in non-small cell lung cancer. In an isogenic context, reactive oxygen species were found to up-regulate autophagy independent of KRAS status. Across seven non-small cell lung cancer cell lines, autophagy responses to starvation varied independent of KRAS status. Among the cell lines up-regulating autophagic flux in response to starvation, KRAS-mutant cell lines increased flux to a greater degree relative to basal levels. Finally, lysosomotropic autophagy inhibitors were characterized in a xenograft mouse model of non-small cell lung cancer. These compounds were safe, tolerable, orally available and elevated in tumors, kidneys, livers and lungs when compared to hydroxychloroquine.
These findings suggest that autophagy responses to starvation should be further investigated in the relationship between KRAS status and autophagy. In addition, my results provide two compounds to be further investigated for autophagy inhibition in vivo. These contributions will inform the field’s aim to improve the understanding and inhibition of autophagy in cancer.
|Commitee:||Cox, Adrienne, Steensma, Matt, Triezenberg, Steve|
|School:||Van Andel Research Institute|
|School Location:||United States -- Michigan|
|Source:||DAI-B 79/11(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Cellular biology, Oncology|
|Keywords:||Autophagy inhibition, Non-small cell lung cancer|
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