Metabolic Adaptations to Autophagy Inhibition in Cancer

Autophagy promotes tumor growth and autophagy inhibition drastically reduces tumor progression in mice. Consequently, there are over 60 clinical trials targeting autophagy in a variety of tumor types. Despite favorable response rates, pre-clinical and clinical studies indicate potential resistance to autophagy inhibition. Recently we created a unique CRISPR/Cas9 assay that includes live-cell imaging to assess autophagy dependence. This assay identified several cancer cell lines that are inherently sensitive to loss of core autophagy genes. However, within these autophagy-dependent cell lines, a proportion of the cells maintain the capacity to survive. Surprisingly, these adapted cells switch to become completely autophagy-independent. Despite loss of this conserved metabolic pathway, the adapted cells eventually proliferate equal to their parental counterparts. We identified several mechanisms that maintain the survival of autophagy-independent cell populations including activation of the master transcriptional regulator, NRF2. We also discovered that autophagy deficient clones can upregulate non-canonical mechanisms to maintain mitochondrial quality control in the absence of the selective autophagic process that targets mitochondria, known as mitophagy. We found that cancer cells that can no longer make functional autophagosomes can still deliver damaged mitochondria to lysosomes via mitochondrial derived vesicles (MDVs). These studies highlighted adaptive mechanisms that cells use to manage organelle quality control in the absence of autophagy. But, autophagy also regulates cancer cell metabolism. Recently, we asked how autophagy-dependent cancer cells adapt their metabolism when this central pathway is blocked. In these studies, we focused on pharmacological autophagy inhibition in pancreatic ductal adenocarcinoma (PDAC), a devastating disease with only a 12% 5-year survival rate. Autophagy is often upregulated in PDAC cells and tumors, suggesting it could be a therapeutic target. We found that PDAC cells that acquire resistance to autophagy inhibition alter their nucleotide metabolism resulting in new therapeutic susceptibilities. Ongoing work in the lab is elucidating the mechanisms behind these adaptations and ideal drug combinations to best leverage these adaptations to improve the use of autophagy inhibition as a patient therapy in PDAC.

This work is funded by NCI/NIH (R00 CA245187-05, DP2 CA290705-01), The Pew Charitable Trusts and The Alexander and Margaret Stewart Trust (00036071), The V Foundation for Cancer Research (V2023-006), The American Association for Cancer Research, The Lustgarten Foundation, and The Emerald Foundation.