UCSF

Oncogene addiction refers to a cancer cell's reliance upon the continued activity of a particular oncogene for survival. This concept has been validated by the success of tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML); a clonal myeloproliferative neoplasm initiated by a single chromosomal translocation event, resulting in the formation and expression of the BCR–ABL fusion gene and protein. TKI therapy results in the inhibition of BCR–ABL tyrosine kinase activity and induces durable responses in the majority of chronic phase CML patients. Here, we have sought to investigate the mechanism(s) responsible for the exquisite sensitivity of CML cells to TKI therapy. Using an isogenic system and patient–derived CML cell lines we have discovered that BCR–ABL–dependent negative feedback is responsible for the attenuation of growth factor–receptor signaling in CML cells. Furthermore, we have found that BCR–ABL–dependent negative feedback persists for an extended period of time following the initiation of dasatinib or imatinib treatment, during which CML cells commit to apoptosis. Experiments performed using a selective MEK inhibitor revealed BCR–ABL–mediated negative feedback to be largely MEK–dependent. This work has also validated the importance of the RAS, STAT5A/B, and S6 signaling pathways in BCR–ABL–mediated oncogene addiction. Additional studies investigating the mechanism of apoptosis in CML cells treated transiently with potent concentrations of BCR–ABL inhibitors revealed that intracellular accumulation of the BCR–ABL kinase inhibitors imatinib and dasatinib results in prolonged BCR–ABL kinase inhibition. Finally, in contrast to the BCR–ABL tyrosine kinase inhibitors, the dual ABL/Aurora kinase inhibitors XL228, danusertib, and MK–0457 appear to mediate cytotoxicity through inhibition of the Aurora kinases. We have shown that expression of BCR–ABL in a cell line harboring a drug resistant mutation in Aurora B confers biochemical cross–resistance to dual ABL/Aurora inhibitors. In conclusion, the work presented here provides novel insight into the mechanisms of action BCR–ABL kinase inhibitors in CML by providing a potential explanation for why BCR–ABL–expressing cells are exquisitely sensitive to TKI therapy, proposing a mechanistic explanation for the effectiveness of transient kinase inhibitor therapy, and identifying the critical cellular target of clinically active dual ABL/Aurora kinase inhibitors in CML cells.