期刊
BMC CANCER
卷 22, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12885-022-10289-w
关键词
ISR; ISRIB; CML; Myeloid leukemia; TKI resistance; STAT5; RAS; RAF; MAPK; PTPN11
类别
资金
- National Science Centre grants: PRELUDIUM [2015/19/N/NZ3/02267, 2013/10/E/NZ3/00673, 2021/41/B/NZ5/04077, 2014/14/M/NZ5/00441]
- TEAM-TECH Core Facility Plus from Foundation for Polish Science - European Union under the European Regional Development Fund [POIR.04.04.00-00-23C2/17-00]
This study reveals that ISR inhibition combined with imatinib treatment can effectively eliminate TKI-resistant leukemia cells. The combined treatment inhibits the STAT5 and RAS/RAF/MEK/ERK pathways, reducing cell resistance.
The integrated stress response (ISR) facilitates cellular adaptation to unfavorable conditions by reprogramming the cellular response. ISR activation was reported in neurological disorders and solid tumors; however, the function of ISR and its role as a possible therapeutic target in hematological malignancies still remain largely unexplored. Previously, we showed that the ISR is activated in chronic myeloid leukemia (CML) cells and correlates with blastic transformation and tyrosine kinase inhibitor (TKI) resistance. Moreover, the ISR was additionally activated in response to imatinib as a type of protective internal signaling. Here, we show that ISR inhibition combined with imatinib treatment sensitized and more effectively eradicated leukemic cells both in vitro and in vivo compared to treatment with single agents. The combined treatment specifically inhibited the STAT5 and RAS/RAF/MEK/ERK pathways, which are recognized as drivers of resistance. Mechanistically, this drug combination attenuated both interacting signaling networks, leading to BCR-ABL1- and ISR-dependent STAT5 activation. Consequently, leukemia engraftment in patient-derived xenograft mice bearing CD34+ TKI-resistant CML blasts carrying PTPN11 mutation responsible for hyperactivation of the RAS/RAF/MAPK and JAK/STAT5 pathways was decreased upon double treatment. This correlated with the downregulation of genes related to the RAS/RAF/MAPK, JAK/STAT5 and stress response pathways and was associated with lower expression of STAT5-target genes regulating proliferation, viability and the stress response. Collectively, these findings highlight the effect of imatinib plus ISRIB in the eradication of leukemic cells resistant to TKIs and suggest potential clinical benefits for leukemia patients with TKI resistance related to RAS/RAF/MAPK or STAT5 signaling. We propose that personalized treatment based on the genetic selection of patients carrying mutations that cause overactivation of the targeted pathways and therefore make their sensitivity to such treatment probable should be considered as a possible future direction in leukemia treatment.
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