Among patients with chronic myeloid leukemia (CML), combining integrated stress response (ISR) inhibition with imatinib may improve leukemic cell eradication, according to preclinical research published in BMC Cancer.

CML is well-known for responding to tyrosine kinase inhibitors (TKIs), including imatinib. Furthermore, previous work shows that patients are sometimes refractory to imatinib and second-generation TKIs. Mutations in BCR-ABL1 are usually implicated in these cases, but the involved pathways include JAK2/STAT5, RAS/RAF/MAPK, and PI3K/Akt/mTOR.

Research from the authors of the present paper also previously suggested that ISR may be involved in disease progression and TKI resistance among patients with CML in blast phase. For this preclinical study, the authors investigated whether ISRIB, a small molecule that inhibits ISR, combined with imatinib may improve imatinib sensitivity in the CML-blast phase setting.

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This study was conducted on CD34-positive cells from patients with CML in blast phase. All cells were obtained through the Institute of Hematology and Blood Transfusion in Warsaw, Poland.

Analysis of using ISRIB and imatinib on these CML cells showed superior eradication both in vitro and in vivo, compared with using either 1 of these agents only. Combining the 2 drugs appeared to block the STAT5 and RAS/RAF/MEK/ERK pathways, suggesting that this strategy may help to overcome treatment resistance.

When the combination was tested on mice with CD34-positive, TKI-resistant CML blasts, leukemia engraftment decreased.

“We postulate that such a strategy can improve therapeutic outcomes in leukemic patients showing TKI resistance related to the hyperactivation of RAS/RAF/MAPK, STAT5 and stress adaptation signaling, and selected based on genetic identification,” the authors wrote in their report.


Dudka W, Hoser G, Mondal SS, et al. Targeting integrated stress response with ISRIB combined with imatinib treatment attenuates RAS/RAF/MAPK and STAT5 signaling and eradicates chronic myeloid leukemia cells. BMC Cancer. 2022;22(1):1254. doi:10.1186/s12885-022-10289-w