Grant: Travel Awards - Institute Community Support

Current treatment for chronic myeloid leukemia (CML) relies on inhibitors such as Imatinib Mesylate (IM) and its newer iterations to target the fusion protein, BCR-ABL, which characterizes CML as a disease. However, BCR-ABL does not always act independently in persisting cell survival, which is why therapeutic resistance and disease relapse often occurs. One critical pathway involved in many cancers, including CML, is the cellular recycling process known as autophagy that becomes turned on when the cancer cells are starved or stressed. Several key autophagy genes are expressed differently in leukemic stem cells compared to there normal counterparts - these are the cells responsible for the repopulating the cancer cells after treatment. The most substantial change is the increased presence of the core autophagy protein ATG4B. The expression of ATG4B is also increased in IM-resistant CML patients compared to those who are IM-responding. Stable reduction of ATG4B in the cell thus reduces autophagy, impairs survival of CML cells, and sensitizes these cells to IM treatment. Novel inhibitors of ATG4B activities are shown to have significant growth inhibition and cell killing benefits in CML cells when combined with IM, and drastically more so when the cells are starved. Inhibiting ATG4B also decreases the activities of the CML stem cells to proliferate into colonies after they have been starved. Mechanistically, inhibition of ATG4B impedes the cells' abilities to use autophagy and respond to the starvation conditions, thus sensitizing the cells to IM therapy. Many other cancer types have identified ATG4B as a cancerous target, so this study will provide insight into the origin of its role in drug resistance and the feasibility of targeting ATG4B in treatment.