Chemotherapy resistance is the major therapeutic barrier in acute myeloid leukemia (AML). To address this issue, the inventors generated a syngeneic mouse model of AML, which we evolved to develop resistance to a front-line chemotherapy regimen. The inventors identified SRRM1 as a critical vulnerability of chemoresistant leukemic cells and identified that PAK1 and CLK kinases are regulators of SRRM1 in chemoresistant AML cells. Human and murine chemoresistant cells were found to be markedly more sensitive to inhibitors of PAKs (FRAX597) and CLKs (TG003 and ML167) compared to their naive counterparts, an effect which was even further enhanced by treatment with cytarabine and daunorubicin. Simultaneous suppression of Clk1 and Pak1 or Clk4 and Pak1 using validated shRNAs and combinations of FRAX597 and TG003, or FRAX597 and ML167 synergized to reduce the growth and the colony-forming capacity of chemoresistant AML cells and sensitized them to chemotherapy. The combined treatment improved overall mouse survival and reduced disease burden in the chemoresistant AML mouse models. Moreover, AML patient cells that were primarily refractory or from a post chemotherapy relapse (n=21) exhibited a higher ex vivo sensitivity to the FRAX597 + TG003 combination in comparison with chemosensitive patients at diagnosis (n=28). Finally, combined PAK1 and CLK inhibition more effectively reduced disease progression in animals transplanted with the relapse sample than in those engrafted with the sample taken at diagnosis. Thus, the present invention relates to combination of PAK1 inhibitors and CLK inhibitors for preventing resistance to chemotherapy in patients suffering from acute myeloid leukemia.