Background: Despite recent advances in
therapies, resistance to
chemotherapy remains a critical problem in the clinical management of
colorectal cancer (CRC). Cancer stem cells (CSCs) play a central role in
therapy resistance. Thus, elimination of CSCs is crucial for effective CRC
therapy; however, such strategies are limited. Autophagy promotes resistance to
cancer therapy; however, whether autophagy protects CSCs to promote resistance to CRC-
therapy is not well understood. Moreover, specific and potent autophagy inhibitors are warranted as clinical trials with
hydroxychloroquine have not been successful. Methods:
Colon cancer cells and tumoroids were used. Fluorescent reporter-based analysis of autophagy flux, spheroid and side population (SP) culture, and qPCR were done. We synthesized 36-077, a potent inhibitor of PIK3C3/VPS34
kinase, to inhibit autophagy. Combination treatments were done using
5-fluorouracil (5-FU) and 36-077. Results: The
5-FU treatment induced autophagy only in a subset of the treated
colon cancer. These autophagy-enriched cells also showed increased expression of CSC markers. Co-treatment with 36-077 significantly improved efficacy of the
5-FU treatment. Mechanistic studies revealed that combination
therapy inhibited GSK-3β/Wnt/β-
catenin signaling to inhibit CSC population. Conclusion: Autophagy promotes resistance to CRC-
therapy by specifically promoting GSK-3β/Wnt/β-
catenin signaling to promote CSC survival, and 36-077, a PIK3C3/VPS34 inhibitor, helps promote efficacy of CRC
therapy.