Potent antiproliferative effect of fatty‐acid derivative AIC‐47 on leukemic mice harboring BCR‐ABL mutation

Therapy based on targeted inhibition of BCR‐ABL tyrosine kinase has greatly improved the prognosis for patients with Philadelphia chromosome (Ph)‐positive leukemia and tyrosine kinase inhibitors (TKI) have become standard therapy. However, some patients acquire resistance to TKI that is frequently associated with point mutations in BCR‐ABL. We previously reported that a medium‐chain fatty‐acid derivative AIC‐47 induced transcriptional suppression of BCR‐ABL and perturbation of the Warburg effect, leading to growth inhibition in Ph‐positive leukemia cells. Herein, we showed that AIC‐47 had anti‐leukemic effects in either wild type (WT)‐ or mutated‐BCR‐ABL‐harboring cells. AIC‐47 suppressed transcription of BCR‐ABL gene regardless of the mutation through downregulation of transcriptional activator, c‐Myc. Reprogramming of the metabolic pathway has been reported to be associated with resistance to anti‐cancer drugs; however, we found that a point mutation of BCR‐ABL was independent of the profile of pyruvate kinase muscle (PKM) isoform expression. Even in T315I‐mutated cells, AIC‐47 induced switching of the expression profile of PKM isoforms from PKM2 to PKM1, suggesting that AIC‐47 disrupted the Warburg effect. In a leukemic mouse model, AIC‐47 greatly suppressed the increase in BCR‐ABL mRNA level and improved hepatosplenomegaly regardless of the BCR‐ABL mutation. Notably, the improvement of splenomegaly by AIC‐47 was remarkable and might be equal to or greater than that of TKI. These findings suggest that AIC‐47 might be a promising agent for overcoming the resistance of Ph‐positive leukemia to therapy.