ULK1 inhibition promotes oxidative stress–induced differentiation and sensitizes leukemic stem cells to targeted therapy

Abstract

ULK1 inhibition increases the sensitivity of leukemia stem cells to TKI therapy by modulating energy and redox balance.

The multifaceted role of autophagy in cancer

“…In terms of specificity, SBI-0206965 may also target FAK and aurora kinases, while ULK101 inhibits members of the CAMK family (Egan et al, 2015;Martin et al, 2018). MRT403 was recently shown to sensitize CSCs from patient-derived CML to imatinib (Ianniciello et al, 2021). This is an Left: Autophagy supports maintenance of charged nucleotide and adenosine pools within the cancer cell.…”

“…In terms of specificity, SBI‐0206965 may also target FAK and aurora kinases, while ULK101 inhibits members of the CAMK family (Egan et al , 2015; Martin et al , 2018). MRT403 was recently shown to sensitize CSCs from patient‐derived CML to imatinib (Ianniciello et al , 2021). This is an exciting development and the sensitivity of CSCs to autophagy inhibition was one of the early drivers for the application of autophagy inhibitors in the clinic (Bellodi et al , 2009).…”

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

“…This shows that TKI may alter tumor energy or metabolic status and adaptively activate autophagy to maintain cell survival. 346 Mitochondrial autophagy is a specific type that can be activated by PTEN-induced kinase 1 (PINK1)-Parkin signaling. Hypoxia/HIF-1α can upregulate miR-210-5p in HCC, downregulating ATPase family AAA domain-containing 3 A (ATAD3A) expression and triggers mitochondrial autophagy via the PINK/Parkin pathway and leads to sorafenib resistance.…”

Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications

“…Intriguingly, the mRNA expression levels of ULK1 in acute myeloid leukemia (AML) samples were analyzed based on TCGA database, and the level of ULK1 is elevated in AML, which was also associated with poor prognosis in AML 217 . Moreover, in chronic myeloid leukemia (CML), inhibition of ULK1 could sensitize leukemic stem cells to tyrosine kinase inhibitor (TKI) 218 . Similarly, P2RY6-mediated autophagic activation of CAMKK2/PRKAA1/ULK1 restores human monocyte differentiation, which is exciting for chronic myelomonocytic leukemia therapy 219 .…”

“…In addition, ULK1-mediated autophagy is one of the causes of drug resistance in TKI treatment of CML, which mediated by maintaining energy and redox balance. Therefore, inhibiting ULK1-induced stress differentiation of leukemia stem cells is a practical approach to enhance the therapeutic effect of TKI on CML 218 , 225 . Moreover, imatinib resistance in the treatment of CML may be caused by grancalcin activation of ULK1-mediated autophagy 120 .…”