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 PKM 2 to PKM 1, 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.