Autophagy as a Limiting Factor to the Effectiveness of Tyrosine Kinase Inhibitors in Blood Cancers

Autophagy, a crucial cellular process involved in maintaining homeostasis through the degradation and recycling of intracellular components, has emerged as a significant player in drug resistance mechanisms in various cancers. This chapter explores the intricate interplay between autophagy and resistance to tyrosine kinase inhibitors in three types of hematological malignancies: chronic myeloid leukemia, Philadelphia-negative myeloproliferative neoplasms, and acute myeloid leukemia. In chronic myeloid leukemia, tyrosine kinase inhibitors targeting the BCR::ABL1 fusion protein, such as imatinib, induce autophagy as a survival mechanism, contributing to therapy resistance. Inhibition of autophagy potentiates the efficacy of tyrosine kinase inhibitors, suggesting a promising strategy for overcoming resistance. Similar observations are made in Philadelphia-negative myeloproliferative neoplasms, where the inhibition of the JAK2/STAT signaling pathway drives autophagy, and the suppression of autophagy enhances the cytotoxic effects of JAK2 inhibitors like ruxolitinib. In acute myeloid leukemia with FLT3 mutations, FLT3 inhibitors induce autophagy, which also promotes resistance to therapy. Combined inhibition of autophagy and FLT3 signaling shows synergistic effects in overcoming resistance, although the complex interactions with leukemia stem cells require further investigation. In summary, this chapter underscores the importance of understanding the role of autophagy in drug resistance and its potential as a therapeutic target in altered tyrosine kinase–driven blood cancers. Future research should focus on elucidating the specific mechanisms underlying autophagy modulation in different cancer types and identifying biomarkers to guide molecularly targeted treatment strategies.