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Tyrosine kinase inhibitors ( TKI ), including imatinib ( IM ), improve the outcome of  CML  therapy. However,  TKI  treatment is long‐term and can induce resistance to  TKI , which often leads to a poor clinical outcome in  CML  patients. Here, we examined the effect of continuous  IM  exposure on intracellular energy metabolism in K562 cells, a human Philadelphia chromosome‐positive  CML  cell line, and its subsequent sensitivity to anti‐cancer agents. Contrary to our expectations, we found that continuous  IM  exposure increased sensitivity to  TKI . Cancer energy metabolism, characterized by abnormal glycolysis, is linked to cancer cell survival. Interestingly, glycolytic activity was suppressed by continuous exposure to  IM , and autophagy increased to maintain cell viability by compensating for glycolytic suppression. Notably, increased sensitivity to  TKI  was not caused by glycolytic inhibition but by altered intracellular signaling, causing glycolytic suppression and increased autophagy, as evidenced by suppression of p70 S6 kinase 1 (S6K1) and activation of  AMP ‐activated protein kinase ( AMPK ). Using another human  CML  cell line ( KCL 22 cells) and  BCR / ABL + Ba/F3 cells (mimicking Philadelphia chromosome‐positive  CML  cells) confirmed that suppressing S6K1 and activating  AMPK  increased sensitivity to  TKI . Furthermore, suppressing S6K1 and activating  AMPK  had a synergistic anti‐cancer effect by inhibiting autophagy in the presence of  TKI . The present study provides new insight into the importance of signaling pathways that affect cellular energy metabolism, and suggests that co‐treatment with agents that disrupt energy metabolic signaling (using S6K1 suppressors and  AMPK  activators) plus blockade of autophagy may be strategies for  TKI ‐based  CML  therapy.

Altered intracellular signaling by imatinib increases the anti‐cancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia cells